Changes to the UK childhood immunisation schedule

Abstract

This article summarises the recommendations by the Joint Committee on Vaccination and Immunisation (JCVI) for a new UK childhood immunisation schedule following the discontinuation of the Hib/MenC vaccine by the manufacturer (currently used at 12 months of age as a booster for these antigens) and the rationale behind these changes to the schedule. From late 2025, when the current stock of Hib/Men C vaccine runs out, Men C vaccination will no longer be offered to toddlers, as the adolescent Men ACWY vaccination programme is expected to effectively sustain herd immunity. To improve herd immunity against polio and sustain Hib control by maintaining the current impact on Hib carriage in toddlers, an 18-month visit will be added to the vaccination schedule, where a booster dose of DTaP/IPV/Hib or DTaP/IPV/Hib/HepB will be offered. The second MMR (measles, mumps, rubella) dose will be advanced from 40 to 18 months to improve uptake, with a recommendation that both MMR doses are offered with varicella immunisation (MMRV (measles, mumps, rubella and varicella)), as addition of varicella to the schedule has been demonstrated to be cost-effective in recent modelling reviewed by JCVI. One of the recently licensed interventions for preventing respiratory syncytial virus (RSV) in infants (a maternal bivalent RSV prefusion F protein vaccine) will be incorporated into the new schedule, which should significantly reduce RSV burden in infants. In addition, higher-valency pneumococcal vaccines with wider serotype coverage may be introduced.

Correspondence to Dr Emily A Lees; [email protected]

SUMMARY

• This article summarises the recommendations by the Joint Committee on Vaccination and Immunisation (JCVI) for a new UK childhood immunisation schedule following the discontinuation of the Hib/MenC vaccine by the manufacturer (currently used at 12 months of age as a booster for these antigens) and the rationale behind these changes to the schedule.

• From late 2025, when the current stock of Hib/Men C vaccine runs out, Men C vaccination will no longer be offered to toddlers, as the adolescent Men ACWY vaccination programme is expected to effectively sustain herd immunity.

• To improve herd immunity against polio and sustain Hib control by maintaining the current impact on Hib carriage in toddlers, an 18-month visit will be added to the vaccination schedule, where a booster dose of DTaP/IPV/Hib or DTaP/IPV/Hib/HepB will be offered.

• The second MMR (measles, mumps, rubella) dose will be advanced from 40 to 18 months to improve uptake, with a recommendation that both MMR doses are offered with varicella immunisation (MMRV (measles, mumps, rubella and varicella)), as addition of varicella to the schedule has been demonstrated to be cost-effective in recent modelling reviewed by JCVI.

• One of the recently licensed interventions for preventing respiratory syncytial virus (RSV) in infants (a maternal bivalent RSV prefusion F protein vaccine) will be incorporated into the new schedule, which should significantly reduce RSV burden in infants. In addition, higher-valency pneumococcal vaccines with wider serotype coverage may be introduced.

Introduction

The immunisation schedule is designed to optimise protection from serious infectious diseases by providing individual direct protection and, where appropriate, sustained population-level control through herd immunity. Recommendations for each vaccine take into account the age-specific risk for a disease/infection (often early childhood), risk of complications, vaccine efficacy and the vaccine’s potential to reduce transmission.¹

Passive protection of neonates and young infants is provided through established maternal programmes for Bordetella pertussis, influenza and SARS-CoV-2. This is particularly important for pertussis given the high infant morbidity, with a case fatality ratio as high as 3% in the neonatal period.² This is of current relevance, as the UK faces a resurgence of pertussis, after a period of exceptionally low activity due to the measures introduced to control the spread of SARS-CoV-2 in 2020 (see online supplemental appendix for details on upcoming changes to prenatal pertussis vaccination).³

The use of an accelerated infant schedule in the UK, commencing at 8 weeks of age, aims to provide early protection against pathogens with a high risk of morbidity and mortality in the very young (eg, B. pertussis, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b (Hib)) with later booster doses to provide ongoing protection. The UK schedule (table 1), which is recognised internationally for its innovation and responsiveness, has been informed by expert review from the Joint Committee on Vaccination and Immunisation (JCVI), and recommendations based on evidence of cost-effectiveness.⁴

Table 1

Current UK complete routine immunisation schedule (adapted from https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule)

Diseases protected against	Prenatal (maternal)	8 weeks	12 weeks	16 weeks	12 months		Eligible groups	3 years, 4 months	12–13 years	14 years
Hepatitis B (HepB)		DTaP/IPV/Hib/HepB	DTaP/IPV/Hib/HepB	DTaP/IPV/Hib/HepB
Diphtheria (D/d), tetanus (T), acellular pertussis (aP), polio (IPV)	dTaP/IPV*							dTaP/IPV		Td/IPV
Haemophilus influenza b (Hib)					Hib/Men C
Meningococcal (Men) disease (groups A, B, C, W and Y)		Men B		Men B		Men B booster				Men ACWY
Rotavirus gastroenteritis†		Rotavirus	Rotavirus
Pneumococcal disease			Pneumococcal conjugate vaccine (PCV13)		PCV booster (PCV13)
Measles, mumps, rubella (MMR)					MMR			MMR
Influenza (yearly from September)	Inactivated influenza vaccine						Live attenuated influenza vaccine; LAIV‡
SARS-CoV-2 (seasonal on current guidance)	mRNA vaccine§						mRNA vaccine§
Cancers and genital warts caused by specific human papillomavirus (HPV) types									HPV¶

*Recommended timing between 16 and 32 weeks’ gestation.

†Rotavirus vaccine only to be given after checking for severe combined immunodeficiency screening result (where offered).

‡All children aged 2 or 3 years, and all primary and secondary school-aged children (reception to year 11) should be offered influenza vaccine, along with children aged 6 months to 2 years in a clinical risk group (https://www.gov.uk/government/publications/influenza-the-green-book-chapter-19); if LAIV contraindicated, use inactivated influenza vaccine.

§Vaccine offered during pregnancy and to children in clinical risk groups during seasonal booster campaigns (https://www.gov.uk/government/publications/covid-19-the-green-book-chapter-14a).

¶Three dose schedule in immunocompromised young people (https://www.gov.uk/government/publications/human-papillomavirus-hpv-the-green-book-chapter-18a.

The UK programme has faced the challenge of a slow but steady decline in childhood vaccination coverage over the past 10 years, with coverage of the three primary doses for the ‘6-in-1’ vaccine in 2 year-olds falling to 91.7% in late 2022 compared with a peak of 94.7% in 2012, and preschool booster coverage declining over the same period.⁵ This has led to the recent emergence and outbreaks of vaccine-preventable diseases, such as measles; with a current outbreak in England, centred around the West Midlands and London.⁶ In early 2022, vaccine-derived poliovirus, capable of causing disease in unvaccinated individuals, was detected in multiple sewage samples in London. To prevent paralytic disease and to help interrupt transmission, a catch-up campaign and the offer of a booster polio vaccine dose to all children aged 1–9 years in London was implemented. There has been no further detection of vaccine-derived poliovirus in sewage samples since November 2022.⁷ In a review of child deaths in England and Wales from 2019 to 2022, delayed or missed vaccination was recorded as a contributory factor in 3% of cases.⁸

A review of the immunisation schedule was prompted by the sole manufacturer of Hib/Men C vaccine ceasing production of this vaccine. The main aim of the review was to sustain the excellent level of Hib control that has been established through the current programme. Furthermore, this provided an opportunity to enhance protection against infection in childhood by the potential adoption of varicella vaccine into the schedule. These changes come alongside the availability of new higher-valency pneumococcal vaccines with wider serotype coverage and new interventions that will reduce the burden of respiratory syncytial virus (RSV) in infancy and have a major impact on paediatric practice. This review examines the likely re-shaping of the schedule in the coming years and the rationale behind these changes.

Withdrawal of Hib/Men C vaccination

The discontinuation of Hib/Men C vaccine by the manufacturer (currently given at 12 months of age), means that a revision to the early childhood immunisation schedule is necessary to ensure ongoing control of Hib. These changes should be implemented before the current stocks of Hib/Men C run out in 2025. There are no alternative products that could replace this vaccine.

The highest incidence of meningococcal infection is in young children, with a peak between 6 months and 2 years of age, and another, smaller peak in incidence in adolescents at 15–19 years of age.⁹ Four serogroups of N. meningitidis are responsible for the majority of invasive meningococcal disease (IMD) in the UK; meningococcal (Men) B, C, W, and Y serogroups. Although increasingly rare due to successful vaccination programmes, IMD continues to have a case fatality ratio of up to 10%, with many survivors experiencing sequelae such as hearing loss, neurological impairment or limb loss.¹⁰ The Men C vaccine programme has evolved over time to successfully control Men C disease; initially with the introduction of an infant vaccine in 1999, with an extensive catch-up programme. Alongside a vaccine efficacy rate of 96%,¹¹ there was a concurrent reduction in attack rate in the unvaccinated population by up to 67%,¹¹ with this herd effect thought to be due to a reduction in Men C carriage in teens and young adults.^{12 13} In subsequent years, Men C doses were scheduled at 12 months and around 14 years to sustain herd immunity.

In 2015, a national outbreak of IMD with a hypervirulent Men W strain occurred, leading to an emergency programme to administer the Men ACWY vaccine to adolescents aged 15–18 years with the aim of reducing transmission across the whole population.¹⁴ This programme, plus the replacement of the routine Men C vaccine at 13–14 years with Men ACWY, led to the decline of Men W cases over the following 2 years.¹⁵ Studies of nasopharyngeal carriage after the introduction of the Men ACWY vaccine demonstrated sustained low levels of Men C carriage, and reduction of W and Y carriage (combined decrease in carriage of C, W and Y from 2.03% to 0.71%), suggesting that this vaccine will also offer indirect protection to other age groups.¹⁶ The other 2015 development was the addition of the Men B vaccine to the national schedule for infants. The Men B vaccine, which has been shown to induce cross-reactive immunity against serogroups C, W and Y in vivo,¹⁷ has further contributed to the decline in rates of IMD in England. In 2019–2020, there were 419 cases of IMD (0.74 cases per 100 000 population), down from 1016 cases in 2010–2011 (1.93 cases per 100 000 population).¹⁸ Social distancing during the SARS-CoV2 pandemic appears to have further accelerated the decline in IMD, with a 75% decrease in the overall incidence of IMD (45 cases April–August 2020, vs 179 over the same period in 2019) for all ages and serogroups.¹⁸ Further data from the UK Health Security Agency demonstrated only one confirmed case of group C IMD between 2021 and 2023^{19 20} despite a reduction in vaccine uptake over the pandemic period. Given the near-absence of IMD caused by Men C (and its projected elimination in the UK by 2040),²¹ once current stocks of Hib/Men C vaccination are depleted, Men C will be removed from the toddler schedule. There is no anticipated change to the infant Men B vaccination programme as protection is acquired directly by individual vaccination, without reducing meningococcal carriage.²² The Men ACWY adolescent vaccination is now considered sufficient to sustain herd immunity across all age groups, supplemented by the potential individual cross-protection from Men B vaccination in children, although it is vital that surveillance of disease and high coverage in the teenage programme is maintained.²³

Addition of 18-month visit to the schedule

Hib vaccination

The Hib-booster dose, currently given as part of Hib/Men C vaccine at 12 months, is known to be critical for the maintenance of herd immunity. In 1992, routine Hib vaccination was given as a 3+0 schedule (at 2, 3 and 4 months), with a single-dose catch-up campaign for those aged 12–48 months implemented at the same time.²⁴ The catch-up campaign led to a rapid decline in Hib disease and carriage-driven transmission. However, from 1999, Hib cases increased in toddlers, due to declining vaccine efficacy over time,²⁵ and as the temporary effect of the catch-up programme on carriage rates declined. In the absence of a booster, Hib transmission was largely driven by children aged 2–4 years,²⁶ with carriage prevalence of 4% in unboosted children of school age.²⁷ A rebound in cases was also observed in adults, due to loss of natural boosting via colonisation.²⁸

This loss of control necessitated a Hib booster campaign for toddlers in 2003, with the introduction of the routine Hib booster at 12 months in 2006.²⁴ The success of the current 3+1 schedule is confirmed by the minimal circulation of Hib in the UK.²⁴ Modelling has suggested that a booster between 1 and 2 years after the primary series (with the last primary dose scheduled at 16 weeks) would provide individual protection against disease and also ensure that nasopharyngeal carriage would remain low, helping to maintain population protection.^{26 29} Therefore, JCVI advised that to sustain Hib control an additional dose of Hib-containing vaccine should be offered at 18 months (table 2). This also offers the advantage of reducing the crowding of vaccines at the 12-month visit and providing a visit to align with the proposed alterations to the MMR (measles, mumps, rubella) schedule as outlined below.

Table 2

Proposed UK complete routine immunisation schedule from 2025 with the addition of 18-month visit

Diseases protected against	Prenatal (maternal)	8 weeks	12 weeks	16 weeks	12 months	18 months	Eligible groups	3 years, 4 months	12–13 years	14 years
Hepatitis B (HepB)		DTaP/IPV/Hib/ HepB	DTaP/IPV/Hib/ HepB	DTaP/IPV/Hib/ HepB
Diphtheria (D/d), tetanus (T), acellular pertussis (aP), polio (IPV)	Tdap*					DTaP/IPV/Hib or DTaP/IPV/Hib/HepB		dTaP/IPV		Td/IPV
Haemophilus influenza b (Hib)
Meningococcal (Men) disease (groups A, B, C, W and Y)		Men B		Men B	Men B booster					Men ACWY
Rotavirus gastroenteritis†		Rotavirus	Rotavirus
Pneumococcal disease			Pneumococcal conjugate vaccine (PCV13)‡		PCV booster (PCV13)‡
Measles, mumps, rubella and varicella (MMRV)					MMRV	MMRV
Influenza (yearly from September)	Inactivated influenza vaccine						Live attenuated influenza vaccine; LAIV§
SARS-CoV-2 (seasonal on current guidance)	mRNA vaccine¶						mRNA vaccine¶
Cancers and genital warts caused by specific human papillomavirus (HPV) types									HPV**
Respiratory syncytial virus (RSV)	RSVpreF vaccine††

*Recommended timing between 16 and 32 weeks’ gestation.

†Rotavirus vaccine only to be given after checking for severe combined immunodeficiency screening result (where offered).

‡Higher-valency pneumococcal conjugate vaccines are under consideration.

§All children aged 2 or 3 years, and all primary and secondary school-aged children (reception to year 11) should be offered influenza vaccine, along with children aged 6 months to 2 years in a clinical risk group (https://www.gov.uk/government/publications/influenza-the-green-book-chapter-19); if LAIV contraindicated, use inactivated influenza vaccine.

¶Vaccine offered during pregnancy and to children in clinical risk groups during seasonal booster campaigns (https://www.gov.uk/government/publications/covid-19-the-green-book-chapter-14a).

**Three dose schedule in immunocompromised young people (https://www.gov.uk/government/publications/human-papillomavirus-hpv-the-green-book-chapter-18a.

††Recommended timing between 28 and 36 weeks’ gestation

MMR coverage

The two-dose MMR schedule was introduced in 1996, with a single dose being 95% effective in preventing clinical measles.³⁰ The second dose protects those who do not respond to the first dose (primary vaccine failure),³¹ and prevents sufficient amounts of susceptible individuals from accumulating to allow the re-establishment of measles transmission. The UK was first declared measles-free by the WHO in 2016 after sustained periods without endemic transmission, but lost elimination status following an outbreak in 2018. This status was regained in 2021,³² however since October 2023, there has been an increase in measles cases across England, with 1368 laboratory-confirmed cases reported as of 30 April 2024.⁶ Two-thirds of these cases (66%) have been in children under 10 years of age, most of whom are unvaccinated. MMR uptake in England (July–September 2023) was 89.8% for the first dose at 1 year of age, and 84.5% for two doses at 5 years,⁵ which falls below the WHO target of ≥95%.³³ There is wide variation in coverage, with some London boroughs having coverage of almost 20% below this target.³⁴ In response to measles outbreaks in the past, some London boroughs brought forward the second MMR dose to 18 months; analysis suggested that uptake in those areas was 3% higher than in areas offering second MMR dose at preschool age.³⁴ Additionally, advancing the second dose of MMR vaccine will benefit children with primary vaccine failure, as they will have a shorter interval prior to protection with the second dose. In order to help improve MMR coverage and support the UK in achieving its commitment to measles elimination, JCVI has advised that the second dose should now be routinely offered at 18 months nationally.

Introduction of varicella vaccine

UK seroprevalence data for varicella zoster virus (VZV) indicates that 90% of children have been infected by 10 years of age.³⁵ Although often seen as a mild and self-limiting condition, some children will develop complications such as secondary bacterial skin/soft tissue infections (particularly caused by group A streptococcus), varicella pneumonitis, encephalitis, stroke and even death.^{35 36} Pregnant women, neonates and the immunocompromised are most at risk of severe varicella disease. Even mild cases result in a significant loss of quality-adjusted life years for caregivers and their children, given the 5-day isolation period necessitated after the onset of the rash.³⁷ Post-infection, VZV remains latent in the sensory neurons for life but can be reactivated; usually decades later, to cause herpes zoster (shingles).³⁵

Modelling reviewed by JCVI in 2009 suggested that a varicella immunisation programme was unlikely to be cost-effective in the UK.³⁵ This was largely driven by the assumption that a reduction in varicella cases would increase shingles incidence among older or immunocompromised adults due to a loss of exogenous boosting (the natural boosting of VZV-specific immune responses on re-exposure to varicella via contact with infected persons). Newer models, incorporating real-world data (including 25 years’ use of the vaccine in the USA, where the projected increase in shingles has not been observed)³⁸ have established that a two-dose universal programme in the UK would be cost-effective, and may even be cost-saving at a low vaccine price.³⁵ Introduction of the vaccine would be complemented by the recent introduction of a more efficacious shingles vaccine, with a phased expansion of this programme to adults over 60 years of age and immunosuppressed adults over 50.³⁹ Indirect benefits of a varicella programme are projected to include a reduction in antibiotic/antiviral prescriptions⁴⁰ and decreased incidence of varicella-related invasive group A streptococcal infection.^{41 42}

The two doses of varicella vaccine can be administered during early childhood in combination with MMR (MMRV (measles, mumps, rubella and varicella)) or as a stand-alone product scheduled concurrently with (or 4 weeks distant from) MMR (MMR+V).³⁵ The first dose of MMRV has been associated with an increased relative risk of febrile seizures within 7–10 days of vaccination, but this does not occur with the second dose.⁴³ However, febrile seizures are benign, usually without risk of long-term health hazards, and the absolute risk is low, at one additional febrile seizure per 2300 vaccinations.⁴³ Moreover, the majority of parents in a survey indicated a preference for a combination vaccine, suggesting that MMRV might have better coverage than MMR+V due to reduced visits and fewer injections, as offered in Italy and Germany.^{44 45} JCVI has advised the Department of Health and Social Care that it would be cost-effective to use a two-dose schedule of varicella vaccine for every child in combination with MMR (MMRV) at 12 and 18 months, alongside a universal catch-up dose for children ≤5 years of age and a targeted campaign for children aged 6–10 years who are susceptible, based on parental recall of no previous VZV infection (this was projected to be more cost-effective than a universal campaign if the accuracy of parental recall was above 25%, which was exceeded in the available literature).^{35 46 47} There will be clear communication on the small risk of febrile seizures to parents of children receiving the first dose of MMRV.

Addition of RSV intervention to the immunisation programme

RSV causes bronchiolitis in infants and can cause severe acute respiratory illness in older adults. Globally, up to 90% of children have experienced RSV infection by 2 years of age.⁴⁸ RSV poses a significant burden on the health system during the RSV ‘season’ from October to March in the UK, resulting annually in up to 33 500 hospitalisations and up to 30 deaths among children under 5 years.⁴⁸ Recurrent RSV infections are common and can occur within one season because post-infection immunity is short-lived.⁴⁹ Infants are most at risk of severe RSV disease in the first 3 months of life,^{50 51} meaning that even early vaccination would not provide an opportunity for sufficient antibody response to cover this at-risk period; therefore passive immunisation is required either by direct administration of monoclonal antibodies to the child or via transplacental antibody transfer following antenatal maternal vaccination.⁴⁸

In 2022/2023, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved two new products for preventing RSV in infants: a monoclonal antibody (nirsevimab), and a maternal bivalent RSV prefusion F protein vaccine (RSVpreF).⁴⁸ Palivizumab; the only RSV monoclonal currently used in the UK, has been limited to at-risk infants due to its high cost, and requirement for monthly injections during the RSV season.⁵² Nirsevimab can be given as a single dose to cover the RSV season due to its extended half-life of 71 days.⁵³ To assess which product would be more suitable for preventing RSV in infants in the UK, JCVI compared multiple parameters for nirsevimab and RSVpreF (table 3). The efficacy of both products was not directly comparable as the trials were designed differently and assessed different endpoints.⁴⁸ Nevertheless, both offered at least 150 days of protection against severe RSV.^53–55 Within months of introduction in Spain, nirsevimab demonstrated an effectiveness of 87% against severe RSV and 66% against all-cause hospitalisations in children during the 2023/2024 RSV season.⁵⁶

Table 3

Comparison of nirsevimab and RSVpreF

	Nirsevimab	RSVpreF
Type of product54 55	Human recombinant anti-RSV monoclonal antibody targeting the fusion (F) protein (conserved in RSV A and B).	Bivalent vaccine containing recombinant prefusion (preF) form of the F proteins from RSV A and B.
Mechanism of protection in neonates and infants54 55	Passive immunisation—antibody directly given to child.	Maternal vaccination during pregnancy with transplacental IgG antibody transfer to the fetus.
Type of antibody response54 55	Monoclonal.	Polyclonal, with a potential for developing immune responses to multiple epitopes.
Efficacy from phase III trials (not head-to-head comparison)48 53–55	RSV-LRTI* hospitalisation 83%. Very severe RSV 76%. RSV-LRTI hospitalisation in neonates 89%. RSV-LRTI hospitalisation in 0–3 months 88%. All cause LRTI hospitalisation 58.0%.	Medically-attended severe RSV-LRTI 82% at 3 months and 69% at 6 months. Medically-attended RSV-LRTI 57% at 3 months and 51% at 6 months. Medically-attended all cause LRTI 7% (−22% to 29%).
Protection in preterm infants54	Efficacy demonstrated in preterm infants ≥29 weeks.	Possibility of inadequate transfer of antibodies depending on the time from maternal vaccination to birth.
Duration of protection54 55	At least 5 months.	At least 6 months.
Safety concerns48 53–55	None.	Potential increased risk of preterm birth—not statistically significant.
No of doses54 55	Single.	Single.
Possible timing of administration48 56	Shortly after birth with opportunities for catch-up in older infants.	From 28 to 36 weeks of gestation.
Route of administration48	Intramuscular injection.	Intramuscular injection (to mother).
Possible time window for delivery in a UK seasonal program48	July to February.	July to December.
Cost-effectiveness in the UK57	Cost-effective at low price.	Cost-effective at low price.
Recent uptake of products with similar delivery in UK58 59 63	Neonatal vitamin K≥95% (which may not accurately predict nirsevimab uptake).	Maternal year-round pertussis vaccine 60–75%. Seasonal influenza vaccine in pregnancy 35%.

*LRTI, lower respiratory tract infection; RSV-LRTI refers to lower respiratory tract infection caused by RSV.

Models suggest that nirsevimab may be slightly more effective overall, but relative cost-effectiveness depends mainly on the price of the products and administration.⁵⁷ A seasonal programme would be more cost-effective than a year-round programme for either product,⁵⁷ however National Health Service England suggested that a year-round programme would be easier to implement,⁴⁸ especially for a programme requiring a specific time window during pregnancy for vaccination. Additionally, data from maternal immunisation programmes suggest that uptake would likely be higher in a year-round rather than a seasonal vaccination programme during pregnancy.^{58 59} Parental acceptance would determine uptake of a product offered to neonates, with recent survey data suggesting that although acceptability was high for both options, acceptability of a maternal vaccine was higher (88% vs 79%, p<0.0001).⁶⁰ Real-world data from monoclonal implementation in 2023 in Luxembourg (84% uptake) and Galicia, Spain (92.6% uptake), suggest that coverage levels approaching those for other neonatal interventions such as intramuscular vitamin K prophylaxis (over 95% uptake) may be achievable.^61–63

JCVI recommended that either nirsevimab or RSVpreF would be appropriate in a universal programme and have a large impact on infant RSV burden, but expressed a preference for a year-round programme for better uptake and more efficient delivery.⁶⁴ The eventual decision is that the maternal RSVpreF vaccine will be introduced to the UK schedule in autumn 2024. Palivizumab will be replaced with nirsevimab for infants currently eligible for RSV prophylaxis, regardless of maternal vaccination status.⁶⁵

Considerations for higher-valency pneumococcal conjugate vaccines

S. pneumoniae is the leading cause of death from bacterial pneumonia in children under 5 years globally.⁶⁶ There are more than 100 serotypes, but vaccine-type (VT) disease and carriage declined in the UK after the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2006.⁶⁷ PCV7 was replaced by PCV13 in 2010, then the 2+1 schedule (two priming doses and a booster) was changed to the 1+1 schedule (priming and booster doses at 3 and 12 months, respectively) in 2020. The latter was based on data showing similar post-booster immunogenicity for both schedules.^{67 68} Indeed, there has been no difference in breakthrough infections or vaccine failure rates between the 2+1 and 1+1 periods, though it should be noted that the SARS-CoV-2 pandemic complicates interpretation.⁶⁹ Before PCV introduction, invasive pneumococcal disease (IPD) was mostly caused by vaccine serotypes, however since the advent of vaccination, serotype replacement is occurring with an increased proportion of disease due to non-vaccine serotypes (NVT). In the UK from April 2022 to March 2023, IPD was confirmed among 378 children aged 0–14 years (with an estimated incidence of 3.9 cases per 100 000 children); 80% of the cases were caused by NVT, while serotypes 3, 19A and 19F accounted for nearly all cases of VT-IPD.⁶⁶ Carriage of these three serotypes persists in asymptomatic children, suggesting incomplete vaccine protection, particularly for serotype 3.^{69 70} Around half of children aged 1–4 years are asymptomatic carriers, mostly of non-PCV13 serotypes,⁷⁰ and are capable of infecting older adults who are susceptible to severe IPD. Newer vaccines with wider serotype coverage could reduce IPD caused by non-PCV13 serotypes.

In 2022, the MHRA licensed PCV15 for use in infants. JCVI evaluated the potential impact of PCV15 on IPD burden if used in the immunisation programme.⁷¹ PCV15 achieved non-inferiority of immunogenicity for all PCV13 serotypes and superiority for the two additional serotypes, 22F and 33F.⁷² Despite meeting the non-inferiority cut-off, antibody titres with PCV15 were slightly lower than PCV13 for all PCV13 serotypes, except serotype 3, for which IgG titres were higher with PCV15.⁷² However, in vivo impact of PCV15 on serotype 3 disease has not yet been demonstrated. The additional two serotypes in PCV15 account for roughly 10% of IPD in the UK.⁶⁹ JCVI concluded that any advantage of PCV15 over PCV13 in the UK schedule is uncertain and advised that either PCV13 or PCV15 could be used in the UK programme.⁷¹

PCV20, which was recently licensed for infants by the European Medicines Agency (EMA),⁷³ contains all PCV13 serotypes alongside seven additional ones. However, the vaccine was only approved by the EMA for use in a 3+1 schedule, whereas PCV13 is licensed in a 2+1 schedule and used in the UK in a 1+1 schedule. The EMA decision is attributed to the lower immunogenicity of the PCV13 serotypes after the second dose when they are included in the higher-valency PCV20 vaccine, meaning that the immune responses do not meet regulatory thresholds for immune responses relative to the previously licensed product.⁷³ If the lower immune responses mean lower protection against the existing PCV13 vaccine serotypes, a higher valency vaccine might cover more serotypes of pneumococcus but with little overall gain in protection as a result of the reduced effectiveness against existing serotypes. Studies are planned in the UK to evaluate PCV15 and PCV20 in a 1+1 schedule. In the near future, JCVI will consider whether PCV20 could replace PCV13 in the immunisation schedule, with new vaccines covering up to 30 different pneumococcal serotypes anticipated in the years ahead (online supplemental table).

Conclusion

Since the announcement of the discontinuation of the combined Hib/Men C vaccine, JCVI has reviewed the current immunisation programme and identified opportunities to sustain herd immunity against these pathogens, mitigate the challenge of declining vaccination coverage and allow for the addition of new vaccines to the schedule. The committee recommends the addition of an 18-month visit during which the Hib booster will be offered in combination with other antigens in the UK programme (either as DTaP/IPV/Hib or DTaP/IPV/Hib/HepB). This combination should sustain or may improve indirect protection against Hib, pertussis and polio. However, Men C vaccination will no longer be offered in early childhood after the current stock is depleted because the ongoing ACWY vaccination of teenagers, who are the main carriers, is expected to sustain herd immunity.

To improve vaccine uptake and prevent further measles outbreaks, JCVI advised that the second dose of MMR should be advanced from 40 to 18 months. Additionally, with new evidence supporting the cost-effectiveness of a universal varicella programme, the committee recommended that two doses of varicella vaccine are to be offered together with MMR at 12 and 18 months. The future schedule includes the committee’s recommendation for the approved RSV maternal vaccine, which is expected to have a large impact on the RSV burden in the UK. PCV13 and PCV15 are expected to have a similar impact if used in the immunisation schedule and licensing and further modelling for higher valency PCVs is awaited. Further revision of the immunisation programme will be necessary as newer vaccines become available, or as surveillance indicates a need to consider alternative options.

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Footnote

X @ajpollard1

OA and EAL contributed equally.

Contributors EAL and OA contributed equally to this paper and have been listed alphabetically. AJP devised the proof outline, with contributions from GA and MER. EAL and OA reviewed the relevant literature and wrote the draft, with the assistance of AJP, GA and MER. All authors reviewed and approved the final manuscript for submission and take responsibility for its content.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests AJP is chair of the UK Department for Health and Social Care’s Joint Committee on Vaccination and Immunisation (JCVI) and was a member of the WHO’s SAGE until 2022. Oxford University entered into a partnership with AstraZeneca for development of COVID-19 vaccines. AJP has had grants with the Gates Foundation, Wellcome, CEPI, MRC, NIHR, AstraZeneca, EC and the Serum Institute of India, all of which were paid to his institution.

Provenance and peer review Commissioned; externally peer reviewed.

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