(C) Our World in Data This story was originally published by Our World in Data and is unaltered. . . . . . . . . . . Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1 + 1) compared with two primary doses and a booster (2 + 1) in UK infants: a multicentre, parallel group randomised co [1] ['David Goldblatt', 'D.Goldblatt Ucl.Ac.Uk', 'Immunobiology Unit', 'Ucl Great Ormond Street Institute Of Child Health', 'London', 'Jo Southern', 'Immunisation Hepatitis', 'Blood Safety Department', 'Public Health England', 'Colindale'] Date: 2022-11 We designed a trial to compare the response to a booster dose of PCV13 when primed with a single PCV13 dose at 3 months of age compared with the standard UK immunisation schedule, where PCV is administered at 2 and 4 months of age with a booster at 12 months. Recent evidence from Australia suggests that in high-income settings, the sustained effect of PCVs is driven mostly by the booster dose of PCV provided in the second year of life.The booster dose contributes to the prevention of acquisition of pneumococci in the nasopharynx and hence interrupts transmission which impacts on all susceptible individuals including those in the first year of life. If one dose of PCV in the first year of life adequately primed for a booster response, it might be possible to reduce the PCV priming schedule without compromising the herd protection afforded by PCV to the unvaccinated population. With the licensure of meningococcal B vaccine (Bexsero, GSK, Rixensart, Belgium) and the decision to introduce it into the UK infant immunisation schedule, there has been a need to seek ways to reduce the number of doses, and overall cost, of vaccines delivered in infancy without compromising disease control. One option would be to reduce PCV13 to a 1 + 1 schedule, giving one priming dose at 3 months of age. Although the immunogenicity of one dose in infancy is expected to be lower than two doses, findings of a UK study with PCV9 showed higher booster responses with fewer priming doses,a finding that is well documented for meningococcal serogroup C conjugate vaccine.With the greatly reduced incidence of PCV13 disease in young children in the UK, and effective herd protection, the potentially increased risk of an invasive pneumococcal infection between 4 and 12 months of age in a child who has only received one dose of PCV13 instead of two will be very low. For example, the incidence of invasive pneumococcal disease in children younger than 2 years due to one of the seven serotypes covered by PCV7 was only 0·38 per 100 000 in 2013/14 epidemiological yearcompared with a pre-PCV7 incidence of 39·05 per 100 000, a 99% reduction. Invasive pneumococcal disease due to the additional six serotypes covered by PCV13 achieved an 89% reduction in incidence in children younger than 2 years within 4 years of PCV introduction, from 12·67 in 2008/10 to 1·43 in 2013/14.Mathematical models have predicted the near elimination of disease due to vaccine serotypes within the next few yearsalthough the experience with PCV13 suggests that some serotypes might be harder to eliminate. Further studies of 1 + 1 schedules in low and middle income countries are currently underway. These, together with invasive pneumococcal disease surveillance and carriage studies will provide a comprehensive evidence base for future decisions about global PCV immunisation strategies. The advantages of reducing the number of doses of PCV from three to two in the infant immunisation schedule include making space in the infant programme for additional vaccines in development and potentially reduced costs. PCVs are the most expensive vaccines in infant schedules and pressure to reduce costs is found universally. Costs saved could be used to purchase other lifesaving vaccines. This immunogenicity trial, the first of its kind to study responses to a booster dose of PCV after just a single priming dose (1 + 1), has shown that responses to most serotypes in PCV13 following a booster dose at 12 months of age are similar or superior to those after a 2 + 1 schedule. This immunogenicity study lays the foundation for a move to a reduced dose 1 + 1 schedule in countries where a mature PCV programme is in place, coverage is high, and vaccine type disease is well controlled. Pneumococcal conjugate vaccine (PCV) was originally licensed as a 3 + 1 schedule and then as a 3 + 0 schedule following pivotal efficacy studies. Immunogenicity studies of a 2 + 1 schedule resulted in the use of this schedule in national immunisation programmes. Evidence subsequently accumulated of the efficacy of a 2 + 1 schedule. To assess whether fewer doses of PCV could be used without compromising efficacy we did a systematic literature review of 14 databases (Embase, PubMed, Biological Abstracts [BA], Pascal Biomed, Global Health, BioAbst/Reports, Reviews, Meetings, Cochrane Library, African Index Medicus [AIM], Western Region Index Medicus [WPRIM], Index Medicus for Eastern Med Region [MEMR], Index Medicus for South-East Asia Region [IMSEAR], Latin America and Caribbean Health Sciences Info [LILACS], Pan-American Health Organisation [PAHO], and IndiaMed [IndMed]), to identify studies that assessed alternative reduced pneumococcal vaccine schedules, published in English from Jan 1, 2010, to Dec 31, 2016, with ad-hoc additions through September, 2017. We found no other studies assessing a single infant dose of PCV followed by a booster in the second year of life. A seven-valent pneumococcal conjugate vaccine (PCV7) providing protection against the most common serotypes causing pneumococcal disease in children in high-income countries was licensed in 2000. The licensing schedule consisted of three priming doses at 2, 4, and 6 months of age and a booster dose at 12 to 15 months (3 + 1 schedule). In the USA, PCV7 was introduced soon after licensure in a 3 + 1 schedule and showed both direct and indirect protection.In the UK, PCV7 was introduced with a two-dose primary series, at 2 and 4 months of age, and a booster dose at 13 months (2 + 1 schedule). This introduction followed a pivotal immunogenicity study suggesting that 2 + 1 was likely to be effective in the UK setting.The advantage of reducing the primary schedule from three to two doses before the booster included space in the infant immunisation for additional vaccines and reduced costs. The 2 + 1 schedule proved highly effective at reducing pneumococcal disease in immunised children in the UK caused by the seven serotypes in the vaccine as well as a reduction in invasive pneumococcal disease in the unvaccinated population.A 2 + 1 PCV schedule is now used in 57 countries around the world. In 2010 the UK, together with many other countries using PCV7, switched from a seven to a 13 valent PCV (PCV13, Prevenar13; Pfizer, New York, NY, USA) with a consequent reduction in overall vaccine type invasive pneumococcal disease due to additional serotypes in PCV13 in vaccine-eligible children as well as older unvaccinated age groups. The funders had no role in study design or the collection, analysis, interpretation, write up of the data or decision to submit the data for publication. The corresponding author had full access to all the data in the study and final responsibility to submit the data. The sample size target was 110 per group with an anticipated 10% loss to achieve 100 evaluable participants per group post booster. Assuming the standard deviation of responses post booster was 0·41 this was sufficient to estimate the ratio of the geometric means between the groups with a precision of 1·3 times for the 95% confidence interval. It was also sufficient to detect 1·5 times differences with more than 80% power at a 5% significance level. For concentrations and titres, results were log transformed and groups 1 and 2 compared by the Kruskal-Wallis test for post-primary responses and by normal errors regression adjusting for sex and interval to blood collection for post-booster responses. The effect of maternal immunisation within each group on concentrations was also assessed by normal errors regression in a post-hoc analysis. Geometric means for each group were calculated with 95% confidence intervals. Proportions above concentration thresholds were compared using Fisher's exact test and proportions calculated within groups with 95% exact confidence intervals. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. Participants were observed for 15 min after each vaccination by a study doctor or nurse, for any immediate reactions. Parents completed a diary card for 5 days from the day of vaccination and recorded all local and systemic adverse events. Unsolicited adverse events and serious adverse events occurring between the day of vaccination and the subsequent visits were recorded with details verified from GP notes as required. The primary endpoint was serotype-specific IgG concentrations measured in blood samples collected at 13 months of age. Secondary outcomes were serotype-specific IgG concentrations measured in blood samples taken at 5 months of age, proportions 0·35 μg/mL or higher of serotype-specific IgG measured in the blood samples taken at 5 and 13 months of age, serotype-specific functional antibody measured in a subset (20%) of blood samples taken at 13 months of age, and the prevalence of carriage of vaccine and non-vaccine pneumococcal serotypes at the time of booster and 6 months later (data not available yet). Up to 5 mL of whole blood were taken at 5 months of age (4 weeks after the second PCV13 dose for one group and 8 weeks after the single priming dose for the other) and 4 weeks after the 12 month visit. Serological analysis was done at the WHO reference laboratory for pneumococcal serology, Great Ormond Street Institute of Child Health, University College London, London, UK. Following extraction from whole blood, sera were stored at −70°C before assay for serotype-specific immunoglobulin G (IgG) to 13 vaccine-type capsular polysaccharides (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). Sera were assayed using the WHO reference ELISA after adsorption with cell wall polysaccharide and 22F polysaccharide at a concentration of 10 μg/mL as previously described in detail.This assay is based on the original Wyeth assay used to generate the correlate of protection of 0·35 μg/mL. The lower limit of assay quantification was 0·15 μg/mL and IgG concentrations of 0·35 μg/mL or higher were considered protective.In a subset of 40 sera functional antibodies to 13 serotypes were measured in a multiplexed opsonophagocytic assay as previously described.Values are expressed as an opsonophagocytic assay titre, equivalent to the reciprocal of the serum dilution required to produce 50% killing of the relevant serotype. Nasal swabs were taken at 12 and 18 months of age to assess pneumococcal carriage but are not reported here. The two trial groups differed according to pneumococcal conjugate vaccine given. Additionally, all participants received routine vaccinations according to the UK schedule: combined diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, and inactivated polio vaccine (Infanrix-IPV-Hib, GlaxoSmithKline, Rixensart, Belgium) at 2, 3 and 4 months, a meningococcal B vaccine (Bexsero, GSK, Rixensart, Belgium) at 2, 4 and 12 months of age, oral rotavirus vaccine (Rotarix, GSK, Rixensart, Belgium) at 2 and 3 months of age, Men C/Hib (Menitorix, GSK, Rixensart, Belgium) at 12 months of age, and mumps, measles and rubella vaccine at 13 months of age. Participants received concomitant paracetamol at 2 and 4 months of age. Infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or at 3 and 12 months of age (1 + 1 schedule) with block randomisation (block size six). Masking was not done for participants and clinical trial staff but individuals were allocated to a study number with its allocated group sequentially. Samples were received in the laboratory coded with no access to individual sample identities. Eligible infants had not received any other vaccinations (with the exceptions of BCG and hepatitis B). Information about the participants' past medical, medication, and vaccination history was collected either by a study paediatrician or from the medical records using a standardised case report form. Information about maternal vaccination during pregnancy with a combined tetanus, diphtheria, acellular pertussis, inactivated polio vaccine (TdaP/IPV) was based on mothers' recall. Written informed consent was obtained from parents before enrolment. Ethical approval was obtained from the Oxfordshire Research Ethics Committee (reference number 15/SC/0387). In this multicentre, parallel group randomised controlled clinical trial, we recruited infants aged between 7 and 12 weeks with no contraindications for vaccination, as defined by Department of Health guidelines. Recruitment was by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services, which is the agency responsible for the central NHS patient database, and via general practices in Gloucestershire and Hertfordshire that are part of the National Institute for Health Research Network. The safety profile for the vaccine was good. 26 serious adverse events were recorded in 21 (10%) individuals across the study period: 18 (n=13) were in the 2 + 1 group and eight (n=8) in the 1 + 1 group. Only one serious adverse event, a high temperature and refusal to feed after the first vaccination visit in a child on the 2 + 1 schedule was considered related to vaccine. GMCs 2 months after a single dose of PCV13 at 3 months of age were significantly lower than those recorded 1 month after two doses for all serotypes except 3 ( table 2 ). When considered as proportions 0·35 μg/mL or higher a significantly greater proportion of children receiving a single priming dose were below the correlate of protection post-primary immunisation ( table 3 ). When analysing the data using serotype specific correlates previously defined by our group,comparison between the groups were similar to those with 0·35 μg/mL or higher as a cut off. Maternal immunisation status had no effect on the post primary GMCs in the 2 + 1 group, but, in the 1 + 1 group, post-primary GMCs were lower in infants of vaccinated mothers (range 6% lower for 6B to 62% lower for 14 and significant (5% level) for 1, 3, 4, 5, 14, 18C, and 19F. Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and 106 were randomly allocated to group 1 (2 + 1 schedule) and 107 to group 2 (1 + 1 schedule). In group 1, 91 serum samples were available for analysis following the visit 1 month after booster immunisation versus 86 in group 2 ( table 1 figure ). Median age at recruitment was 60 and 59 days, respectively for the two groups and the median age at the time of the booster was 371 days for both groups. The groups were evenly matched in terms of age at booster, although the number of infants with a long interval to the post-booster blood sample was higher for group 1 (seven vs two >42 days). There was also a chance imbalance in sex with 60 boys in group 1 (57%) and 49 boys in group 2 (46%), with serotype-specific responses between 10 and 26% lower in boys post booster. For these reasons post booster p values comparing groups are presented from the planned analysis in which there was adjustment for sex and interval to blood sample. Discussion 10 Jodar L Butler J Carlone G et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. 6 Borrow R Goldblatt D Finn A et al. Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United Kingdom. This is the first study to formally compare booster responses to PCV after one or two priming doses of PCV provided to infants in the first year of life. Booster responses to five of the 13 serotypes were similar between the groups whereas responses to four serotypes were better in the single priming dose group compared with those receiving PCV according the UK national immunisation schedule. Responses to the remaining four serotypes, 6A, 6B, 18C and 23F, were lower in the 1 + 1 group but 1·8 (18C) to 9·2 (6B) times higher than the equivalent serotypes specific GMCs measured at 5 months of age after two priming doses. While a correlate of protection after boosting is not defined, a correlate of protection for PCV is accepted based on IgG concentrations after primary immunisation.Analysing the proportions higher than this correlate (0·35 μg/mL) in both groups after boosting showed that both achieved similar proportions higher than 0·35 μg/mL and were close to 100% for most serotypes. Enhanced boosting after fewer primary doses has been described before for meningococcal C conjugate vaccinesand was shown again for some serotypes in this study. The underlying mechanism and the reason why this phenomenon only affects certain serotypes remains unclear. 2 Whitney CG Pilishvili T Farley MM et al. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. 12 Andrews NJ Waight PA Burbidge P et al. Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study. As expected, the immunogenicity of a single dose at 3 months of age was significantly inferior to two doses administered at 2 and 4 months of age although it is possible that responses would have been slightly higher had they been measured at 4 rather than 8 weeks post vaccination. Despite low responses to a single dose of PCV in infancy, a single dose is associated with significant direct protection, though less than with a two or three dose priming schedule. In the USA findings of a case-control studyof PCV7 showed efficacy for one dose given to infants younger than 7 months of 73% (95% CI 43–87) whereas in the UK, one dose of PCV13 given to infants younger than 12 months for the serotypes in PCV13 but not PCV7 had an efficacy of 60% (95% CI 12–82).The effect of maternal immunisation with a diphtheria toxoid-containing vaccine significantly reduced the post-primary responses to some serotypes in the 1 + 1 group in our study so the level of protection after a single dose might be less than reported previously in the absence of maternal immunisation. There was no effect of maternal immunisation on post-booster responses in either the 1 + 1 or 2 + 1 groups. 3 Goldblatt D Southern J Ashton L et al. Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers. Establishing an evidence base for reducing PCV doses given during primary immunisation from two or three to a single dose followed by a booster towards the end of the first or in the second year of life, could help countries with a mature PCV programme and little vaccine type invasive pneumococcal disease to move to a reduced dose schedule. A reduction from a total of three to two PCV doses would have potentially important consequences for both specific countries making the change and the global community, by reducing the number of vaccines administered at immunisation visits and reducing the overall cost of preventing pneumococcal disease. Extended PCV vaccines have been licensed on immunogenicity alone and thus there is an established precedent for using immunogenicity studies to inform vaccine policy. An example of this was the evaluation of a 2 + 1 PCV schedule in the UK infant immunisation programme at a time when 3 + 1 was the licensed schedule.Demonstrating likely efficacy of a 2 + 1 schedule followed by implementation and evaluation of the impact of such a schedule in the UK has provided additional confidence that immunogenicity studies can adequately predict performance of PCV vaccines and has led to many countries either switching to, or introducing PCV in a 2 + 1 schedule. 5 Waight PA Andrews NJ Ladhani SN Sheppard CL Slack MP Miller E Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. 13 van Hoek AJ Sheppard CL Andrews NJ et al. Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. 5 Waight PA Andrews NJ Ladhani SN Sheppard CL Slack MP Miller E Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. 13 van Hoek AJ Sheppard CL Andrews NJ et al. Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England. 14 Feikin DR Kagucia EW Loo JD et al. Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites. 15 Wroe PC Lee GM Finkelstein JA et al. Pneumococcal carriage and antibiotic resistance in young children before 13-valent conjugate vaccine. 16 Moore MR Link-Gelles R Schaffner W et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. 17 Yildirim I Little BA Finkelstein J et al. Surveillance of pneumococcal colonization and invasive pneumococcal disease reveals shift in prevalent carriage serotypes in Massachusetts' children to relatively low invasiveness. While it is recognised that a single dose provides less protection against disease and carriage than a two-dose or three-dose primary series, in high-income countries with mature vaccine programmes individual protection is rarely required because the probability of exposure to vaccine-type infection is low. In England and Wales where the incidence of PCV7-type invasive pneumococcal disease in children younger than 2 years reduced by 99% within 8 years of PCV introduction,there was near elimination of PCV7 serotype carriage both in children and in older age groups.The resulting herd immunity was reflected in an overall reduction (all ages) of 86% in invasive pneumococcal disease covered by PCV7 by 2013/14.For the extra six serotypes in PCV13 (ie, those unique to PCV13 and not found in PCV7, known as PCV13-7) carriage prevalence in individuals younger than 60 years in England and Wales fell from 18·9% in 2008/09 to 0·6% by 2012/13, with an associated overall reduction in invasive pneumococcal disease covered by the PCV13-7 serotypes of 69%.Serotypes 19A and 3 were the two that accounted for the low level of persisting PCV13-7 carriage. In the USA, 7–9 years after the introduction of PCV7, there was a 97% reduction in the incidence of vaccine-type invasive pneumococcal disease in children younger than 5 years compared with the pre-PCV7 baselinewhile there was near elimination of nasopharyngeal carriage of PCV7 serotypes amongst healthy children in Massachusetts.Following PCV13 introduction in the USA, PCV13-7 invasive pneumococcal disease reduced by 93%and carriage of the relevant serotypes has reduced amongst children in Massachusets. 18 Sa-Leao R Nunes S Brito-Avo A et al. High rates of transmission of and colonization by Streptococcus pneumoniae and Haemophilus influenzae within a day care center revealed in a longitudinal study. 19 Althouse BM Hammitt LL Grant L et al. Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities. 20 Flasche S Van Hoek AJ Goldblatt D et al. The potential for reducing the number of pneumococcal conjugate vaccine doses while sustaining herd immunity in high-income countries. 12 Andrews NJ Waight PA Burbidge P et al. Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study. 21 Pennington SH Pojar S Mitsi E et al. Polysaccharide-specific memory B cells predict protection against experimental human pneumococcal carriage. , 22 Ferreira DM Neill DR Bangert M et al. Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. Therefore, the success of a 1 + 1 PCV schedule relies on the timely provision of a booster dose and the schedule's ability to sustain indirect protection in a mature PCV programme. Toddlers and older children between the age of 12 and 36 months of agerather than infants, are thought to be the major spreaders of pneumococci to their siblings and parents. Vaccinating this age group is therefore thought to be critical in establishing and sustaining indirect protection, hence reassurance is required that the booster response following a single priming dose would sustain vaccine efficacy against acquisition of carriage.As we have shown, for nine of the 13 serotypes in PCV, booster responses following a single priming dose are equivalent or superior to those after two priming doses so no reduction in the prevention of vaccine type nasopharyngeal acquisition would be anticipated. For the four serotypes where the 1 + 1 schedule led to inferior IgG responses, the lowest serotype specific correlates of protection (range 0·14–0·20 μg/mL)have been noted. Whereas at a population level less IgG is required to provide protection against infection with these serotypes, the association between circulating IgG and the prevention of carriage acquisition is unclear. The true mechanisms for preventing nasopharyngeal acquisition are not known and may be related to the local production of IgG by memory B cells resident in the nasopharynx rather than circulating IgG. 23 Collins S, Sheppard C, Litt D, et al. Trends in invasive pneumococcal disease over time: England and Wales 2000/01 to 2014/15. 10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-10): Glasgow, Scotland, 2016. 24 Miller E Andrews NJ Waight PA Slack MP George RC Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine. It is possible that reduced primary responses to a single dose allows continued vaccine type carriage in the first year of life before boosting. This might be especially relevant for those vaccine serotypes that persist, albeit at a low level in the community and continue to cause disease. A relevant example in the UK setting would be serotypes 3 and 19A, which continue to cause cases of invasive pneumococcal disease in all age groups. For serotype 3, no significant protection has been demonstrated in England and Wales with the 2 + 1 schedule, and invasive pneumococcal disease due to this serotype has been increasing since 2013/14.For 19A, for which there has been a major population impact, direct protection following a single dose administered below the age of 12 months was relatively low (38%, 95% CI −218 to 89).Reduced primary immunity might lead to an increase in cases in the first year of life although the extent of that increase and whether the number of expected additional cases would offset the cost savings realised by reducing the number of PCV doses administered is not clear. 25 Kwambana-Adams B Hanson B Worwui A et al. Rapid replacement by non-vaccine pneumococcal serotypes may mitigate the impact of the pneumococcal conjugate vaccine on nasopharyngeal bacterial ecology. 26 Kamng'ona AW Hinds J Bar-Zeev N et al. High multiple carriage and emergence of Streptococcus pneumoniae vaccine serotype variants in Malawian children. 27 Bojang A Jafali J Egere UE et al. Seasonality of pneumococcal nasopharyngeal carriage in rural Gambia determined within the context of a cluster randomized pneumococcal vaccine trial. 8 Jayasinghe S Menzies R Chiu C et al. Long-term impact of a “3+0” schedule for 7- and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in Australia, 2002–2014. While we have emphasised the importance of the booster dose in sustaining the indirect effect, in most low and middle income countries, PCV is administered according to the WHO Expanded Programme of Immunisation schedule where primary vaccination is scheduled to occur at 6, 10, and 14 weeks of age with no later booster dose (3 + 0). The long term impact of 3 + 0 schedules is difficult to gauge as few low and middle-income countries have established, high quality, population based invasive pneumococcal disease surveillance in place and sustained high coverage of PCV over a prolonged period of time. In The Gambia, where PCV7 was introduced into the routine programme in 2009 and replaced in 2011 by PCV13 and where vaccine coverage is high, the carriage prevalence of PCV7 serotypes appears to be persisting at around 20%.This persistence of carriage is in contrast to the UK and the USA where PCV7 carriage has been almost eliminated. The epidemiological characteristics of pneumococcal carriage and disease in many low-income and middle-income countries differs from that in high-income countries in a number of ways including the relatively high carriage frequencies in infants younger than 1 yearand adults.It is therefore unclear what the contribution of the absence of a booster dose is to the observed persistence of PCV7 vaccine type carriage in infants in The Gambia. In high income settings it would appear from the experience in Australia that a booster dose is integral to optimising the long-term impact of PCV.However, it would be simplistic to compare the impact of PCV in high income countries with that seen in low and middle income countries and to attribute the difference in vaccine type disease control and carriage reduction solely to the presence or absence of a booster dose. 28 GAVI Alliance, Advance Market Commitment for vaccines (AMC) Advance market commitment for pneumococcal vaccines. Annual report 1 January–31 December 2016. The Gavi Alliance currently supplies vaccines and vaccine support for the world's poorest countries and projects a spend on pneumococcal vaccines between 2011 and 2020 of US$4·7 billion (2016 pneumococcal AMC annual report). Most countries receiving Gavi Alliance support use a 3 + 0 schedule. An eventual shift to a 1 + 1 therefore has very significant financial implications with a reduction of approximately one third in vaccine costs. This cost reduction is particularly relevant for those lower middle income countries who are soon to graduate from Gavi Alliance eligibility and will thus be required to fund their own PCV programmes. By 2020, 30 of the original GAVI Alliance eligible countries will have either graduated or be graduating and a potential one third reduction in the cost of PCV for such countries could be critical for sustaining PCV programmes. Further evaluation will be required to establish the relevance of our findings to diverse epidemiological settings. It should be noted that this was an immunogenicity study and therefore the translation of immunogenicity findings to eventual efficacy when a 1 + 1 schedule is introduced is unclear. Furthermore, the study was done in the UK and therefore its applicability to low and middle income country settings should be interpreted with caution and ideally followed up with further immunogenicity studies in relevant settings. 29 Immunisation JCoVa JCVI Statement on the use of meningococcal C vaccines in the routine chilfhood immunisation programme. In conclusions, our data suggest that booster responses following a 1 + 1 schedule are unlikely to compromise long-term control of invasive pneumococcal disease when administered in a setting where PCV coverage, particularly for the booster dose, is high at local, regional and national level, PCV has been used for some years, and pneumococcal disease and carriage of vaccine serotypes has already been controlled in all age groups. These conditions are currently likely to only be met in high-income countries and thus extrapolating this study's finding to the current situation in low and middle-income countries should be made with caution. Should a 1 + 1 schedule be considered adequate, the ideal conditions and timing favouring a switch from the current schedule still need consideration. Key to the decision to move to a 1 + 1 schedule would be acceptance of the role and importance of the indirect effect seen with conjugate vaccines. The UK Government's vaccine committee took this into account when removing the second dose of the three-dose monovalent meningococcal C conjugate vaccine schedule from infancy to adolescence, when carriage prevalence is likely to be highest.Similar recognition of the role and importance of the indirect effect will be key to underpinning any potential changes to the UK PCV infant immunisation programme. A number of randomised controlled studies comparing a 1 + 1 PCV schedule with existing immunisation schedules in India, South Africa, Vietnam, and The Gambia are currently underway. These, together with invasive pneumococcal disease surveillance and carriage studies will provide a comprehensive evidence base for future decisions about global PCV immunisation strategies. 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