Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule

Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule Rachel J Oidtman , Natalie Banniettis , Jessica Weaver , Ian R Matthews , Dionysios Ntais , Giulio Meleleo , Tufail M Malik , View ORCID Profile John C Lang , Oluwaseun Sharomi doi: https://doi.org/10.1101/2025.03.19.25324262 Rachel J Oidtman 1 Merck & Co., Inc. , Rahway, NJ, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: rachel.oidtman{at}merck.com oluwaseun.sharomi{at}merck.com Natalie Banniettis 1 Merck & Co., Inc. , Rahway, NJ, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jessica Weaver 1 Merck & Co., Inc. , Rahway, NJ, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ian R Matthews 2 MSD (UK) Ltd, Value, Access, and Devolved Nations (VAD) , London, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dionysios Ntais 2 MSD (UK) Ltd, Value, Access, and Devolved Nations (VAD) , London, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Giulio Meleleo 3 Wolfram Research, Inc. , Champaign, IL, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tufail M Malik 1 Merck & Co., Inc. , Rahway, NJ, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site John C Lang 4 Merck Canada Inc. , Kirkland, Quebec, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for John C Lang Oluwaseun Sharomi 1 Merck & Co., Inc. , Rahway, NJ, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: rachel.oidtman{at}merck.com oluwaseun.sharomi{at}merck.com Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Introduction In 2020 the UK National Immunization Programme reduced the pediatric dosing schedule for pneumococcal vaccination with PCV13 from 2 doses in infancy followed by a toddler dose (2+1 schedule) to 1 dose in infancy followed by a toddler dose (1+1 schedule). Real world data on vaccine effectiveness (VE) against invasive pneumococcal disease (IPD) under the reduced dosing schedule is not available, nor is data on VE associated with higher valency vaccines, including PCV15. This analysis investigates changes in projected disease outcomes associated with potential reductions in VE against IPD with PCV13 and PCV15 under the 1+1 reduced dosing schedule. Methods A previously published dynamic transmission model was employed to project population-level IPD incidence under 1+1 pneumococcal vaccination dosing of children <2 years old with two different vaccine formulations, with maintenance of current adult and at-risk vaccination programs, under a range of assumptions regarding reduction of VE against IPD, over a 20-year timeline following the switch to the 1+1 schedule. A probabilistic sensitivity analysis was performed to evaluate the sensitivity of model outcomes to potential changes in VE against IPD. Results Relative to 2019 estimates, overall IPD incidence was predicted to increase over the time horizon for both PCV13 and PCV15 programs, however vaccination with PCV15 was estimated to lead to a smaller increase over all age groups than vaccination with PCV13. Both vaccine formulations led to projected decreases in IPD attributed to common PCV13/PCV15 serotypes in children <2 years old. Sensitivity analyses reflect results were robust to potential changes in VE against IPD. Conclusions The current analysis predicts switching the routinely administered pediatric pneumococcal vaccine from PCV13 to PCV15 within the UK’s 1+1 dosing schedule would not only reduce IPD in the pediatric population but would also lead to population-level reductions in IPD due to indirect protection. INTRODUCTION Pneumococcal disease (PD), caused by Streptococcus pneumoniae , leads to significant morbidity and mortality, especially in young children. 1 Preventative pneumococcal conjugate vaccines (PCVs) targeting clinically relevant serotypes are recommended for routine administration in early childhood. PCV7 was initially licensed 25 years ago as a 4-dose schedule, with 3 doses in infancy followed by a toddler dose (3+1). 1 Based on immunogenicity data supporting reduced dosing schedules, coupled with economic pressures and crowded childhood immunization schedules, the United Kingdom (UK) became the first country to adopt PCV7 in a 3-dose (2+1) schedule in their national immunization programme (NIP) in 2006. 2 , 3 In the adult population, PPSV23 has been widely used for adults aged ≥65-years-old since 2003. 4 Before the introduction of PCVs in the UK, overall invasive pneumococcal disease (IPD) incidence was 14.8 per 100,000, with the PCV7 serotypes accounting for approximately half of the IPD disease burden. 4 By 2010, the overall incidence of IPD had dropped to 10.1 cases per 100,000, with PCV7 serotypes comprising 14% of IPD. 4 However, a relative increase in the proportion of non-vaccine type (NVT) PD led to the adoption of PCV13 in 2010, which covered 58% of the disease burden at that time. 4 By 2019-2020, overall disease incidence reached a low of 9.4 per 100,000 and NVT IPD comprised about 81% of the disease burden. 1 The reduction in overall IPD, with NVT driving the residual burden of disease, motivated two changes for the pediatric PCV NIP – the move to a 1+1 dosing schedule, and the interest in switching to a higher valency PCV. These changes were further supported by several factors: (1) high vaccine coverage rates leading to good control of vaccine type (VT) PD; 3 (2) a 2018 randomized control study by Goldblatt et al which demonstrated similar immune responses to PCV13 in 2+1 and 1+1 dosing schedules; 2 and (3) a 2019 modeling study by Choi et al projecting the incidence of IPD and non-bacteremic pneumococcal pneumonia (NBPP) would not be affected by a reduction in dosing schedule. 5 The decision to move to a 1+1 dosing schedule was not without risk, as fewer doses in infancy, when the immune system is immature, may lead to subpar protection and breakthrough disease. A separate modeling study conducted by Wasserman et al explored the projected potential effects of switching to a 1+1 PCV13 dosing schedule in the UK. 6 This study estimated the reduction of the number of infant doses was projected to lead to an increase in IPD cases over a 10-year time horizon, with the greatest increases occurring in infants and in older adults, also resulting in an increase in deaths. 6 This finding was consistent with the results of the randomized control study by Goldblatt et al which supported the switch to a 1+1 dosing schedule while also noting this potential risk. 2 In January of 2020, the 1+1 reduced dosing schedule was implemented in the UK, with the infant dose administered at 12 weeks of age and the toddler dose at 1 year. 7 Contagion control measures for the COVID-19 pandemic were implemented soon after this switch, rendering it difficult to estimate the effects of this policy change due to the overall reduction of PD. A real-world observational study, published in 2024, indicated that the overall IPD incidence in 2022/23 had decreased in the years since implementation of the 1+1 dosing schedule (which included the period when COVID-19 pandemic measures were in effect). 1 However, VT IPD incidence increased over this period, which may hint at the fact that the immune response for a 1+1 schedule is insufficient to maintain prior levels of control of VT IPD, though it is difficult to draw conclusions given the confounding effects of COVID during this timeframe. 1 The percentages of PD due to VT and NVT in the UK are still substantial and warrant the consideration of higher valency PCVs in the pediatric NIP. Due to the reduction of serotype-specific immunogenicity as more serotypes are added to a PCV (“immunogenicity-creep”), there is risk of reduced effectiveness of higher valency PCVs. 8 , 9 Nevertheless, the replacement of PCV7 with the higher-valency PCV13 in the UK did not lead to an increase in VT disease. 4 Two new expanded valency PCVs were recently licensed in the UK – PCV15 (Vaxneuvance TM , Merck & Co., Inc., Rahway, NJ, USA) and PCV20 (Prevnar 20 TM , Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer, Inc.) – which provide protection against additional NVT serotypes. 1 The clinical impact of these new PCVs and their potential for immunogenicity-creep expected in 1+1 dosing remains to be seen. The confluence of information from immunogenicity studies on reduced dosing schedules, epidemiological data, transmission models, and the impact of the COVID 19 pandemic on the epidemiology of infectious diseases paints a confusing picture of the potential effectiveness of a 1+1 dosing schedule for pediatric pneumococcal vaccination in the UK with PCV13, and potentially with higher valent PCVs. This analysis employs a previously described and calibrated model to explore the potential impact of reduced vaccine effectiveness (VE) against disease resulting from a reduced dosing schedule, with pediatric vaccines PCV13 and PCV15. METHODS Model overview The dynamic transmission model used in this analysis was a published deterministic, age-structured, population-level model, accounting for (1) demographic components, including births, deaths, and aging, and (2) carriage transmission dynamics in the presence of historical vaccine introduction. 10 , 11 The demographic model assumed a constant population size and included age structure in the form of four age groups: <2-, 2-4-, 5-64-, and ≥65-year-olds. 12 , 13 Mixing among populations of different ages is particularly relevant for S. pneumoniae transmission and was accounted for with a previously published mixing matrix. 14 The epidemiological model was based on a system of ordinary differential equations and distinguished between pneumococcal carriage (single, double, and triple) and disease, as well as vaccination status. The progression from pneumococcal carriage to pneumococcal disease was modeled through an age-, serotype class-(STC), and vaccine-status-specific relationship, wherein disease occurs in some fraction of carriage episodes ( Supplementary Figure S1 ). Given the relative infrequency of transmission from adults to children, the simplifying assumption was made that no transmission occurred from adults to children. 15 For the purpose of this model, pediatric age strata were comprised of <2- and 2-4-year-olds and adult age strata were comprised of 5-64- and ≥65-year-olds. A complete description of the model, inputs, parameter estimates, and calibration results was provided in Oidtman et al. 2025. 11 In brief, the model was calibrated using the Nelder-Mead simplex method implemented in the NMinimize function in Mathematica 13.3.1 (Wolfram Research, Champaign, IL) to minimize a weighted sum of squared errors objective function over the annual age- and STC-specific IPD incidence data. 16 During the calibration, four sets of age- and STC-specific parameters were estimated: vaccine efficacy against carriage, carriage acquisition rate given contact, invasiveness (case-to-carrier ratio), and pairwise competition between STCs. 11 For the competition parameters, historical replacement dynamics were used to calibrate the specific STC-STC combinations. In the absence of observed data on replacement dynamics, such as is the case between historical novel VTs in PCV13 and the novel VTs in PCV15, there was assumed to be no explicit competition. Inputs and data sources Annual age- and serotype-specific IPD incidence data for 2000-2019 were provided by the UK Health Security Agency (HSA) 4 and were used as a model calibration target for the pre-PCV NIP era steady state (2000-2005) and the vaccine period (2006-2019). As the model is driven by carriage dynamics, S. pneumoniae carriage data from 2006 were used as a baseline target for the pre-PCV NIP era. 17 , 18 Serotype-specific IPD and carriage data were aggregated into 11 STCs based on the inclusion of different serotypes in different vaccines to calibrate to historical data ( Table 1 ). 19 , 20 View this table: View inline View popup Download powerpoint Table 1. Serotype classes (STCs) with respective serotypes (STs) included in each class. Shading indicates inclusion in different vaccines. The vaccination group indicates how serotype classes were grouped for visualization purposes. Note that serotype 3 was included in a stand-alone STC due to evidence of limited immunogenicity response from vaccines. 21 Serotype and age-based data on VE against IPD were available for PCV13 22 and PPSV23. 23 Given the lack of real-world evidence for VE against IPD for novel PCV15 serotypes, VE was estimated as the weighted average (weighted by the number of STs in each PCV grouping) from prior vaccine-specific estimates (Supplementary Tables S1-S2). Base case values for VE against IPD ( Table 3 ) were calculated by applying a 12.8% average reduction in PCV13 VE under a 2+1 schedule, based on an observational study by Savulescu et al; 22 additional details are provided in the Sensitivity analysis subsection. Data on serotype-specific carriage clearance rates (i.e., the inverse of the duration of carriage) were available from studies from multiple countries and settings, 24 – 36 which were averaged over serotype and age to obtain aggregate inputs into the model (more details available in Tables S3-S5 in Oidtman et al. 2025 11 ). Data on vaccination coverage rates by age were available from the HSA (Supplementary Tables S3-S5). 37 Projection scenarios The calibrated model was used to evaluate the impact of implementing a 1+1 dosing schedule among children <2 years old with either PCV13 or PCV15 beginning in 2020. Both scenarios assumed a continuation of PPSV23 in older adult and risk group populations. In both pediatric and adult populations, it was assumed VCR levels from 2019 remained constant into the projected 20-year time horizon (Supplementary Tables S3-S5). Reductions in pneumococcal disease or contact patterns arising from protection measures enacted during the COVID-19 pandemic were not accounted for in these projections. Model projection scenarios are summarized in Table 2 . View this table: View inline View popup Download powerpoint Table 2. Projected vaccination scenarios for PCV13 and PCV15 in a 1+1 dosing schedule. Sensitivity analysis To explore uncertainty in the potential reductions in VE against IPD associated with a reduced pediatric dosing schedule, a probabilistic sensitivity analysis (PSA) was performed which varied the vaccine effectiveness against IPD in both PCV13 and PCV15. This analysis did not consider potential reductions in vaccine efficacy against carriage. Potential reductions in VE against IPD resulting from the adoption of a reduced dosing schedule were informed by the estimated 12.8% average reduction in PCV13 VE when shifting from a 3+1 schedule to a 2+1 schedule, based on an observational study by Savulescu et al of PCV13 VE against IPD in pediatric populations in Europe. 22 The range in VE values for the PSA was defined as follows: the upper limit was set to equivalency, such that the VE would be equivalent in a 1+1 and 2+1 dosing schedule; the mean value was set to the average 12.8% reduction following Savulescu et al.; 22 and the lower limit was set to a maximum reduction informed by doubling the average reduction ( Table 3 ). View this table: View inline View popup Download powerpoint Table 3. Vaccine efficacy values used for the probabilistic sensitivity analysis. 12.8% average reduction corresponds to the reduction from 0.897 (3+1) to 0.782 (2+1) as described in Savulescu et al. 22 The VEs were drawn from beta distributions with ranges approximately equal to those described in Table 4 and parameters were varied in a Latin Hypercube Sampling method with a total of 100 random samples. 38 The PSA did not consider differences in VE by vaccine, for example a reduced VE in PCV7 STs was applied equally to both PCV13 and PCV15. View this table: View inline View popup Download powerpoint Table 4. Projected IPD incidence (per 100,000) by serotype grouping in <2-year-olds. IPD incidence at the start of the projection (0 years) and at the end of the 20-year time horizon, with administration of either PCV13 or PCV15 in the <2-year-old population. The mean projections of IPD (over 100 Latin hypercube samples), percent change from start of projections, and the 90% intervals (5% and 95% quantiles) are included. NA values indicate the same value across all PSA realizations and therefore no informative interval. NA – not applicable RESULTS Model calibration The model was able to closely reproduce historically observed IPD dynamics, including the decline in incidence of VT IPD following the introduction of PCV7 and PCV13 and the subsequent increase of NVT IPD due to serotype replacement. In the <2- and 2-4-year-old populations, there were some observed dynamics that the model was not able to completely reproduce, such as the large increases of non-PCV15 serotypes beginning in 2014-2015 ( Figure S2 ). The root mean squared error (RMSE) was used post hoc to compare model predictions to surveillance data by age, year, and STC, wherein an RMSE closer to zero indicates a better fit while a higher value indicates more error. The RMSE values were 1.47, 0.597, 0.312, and 1.29 for the <2-, 2-4-, 5-64-, and ≥65-year-old age groups ( Figure S3 ). Across all age groups, the RMSE was 1.03. A complete description of the model fitting results and parameter estimates are available in Oidtman et al. 2025. 11 Projections of IPD in children less than two years old For both PCV13 and PCV15, the model projected an increase in overall IPD incidence in children less than two years old over a 20-year time horizon as a consequence for switching from a 2+1 to a 1+1 dosing schedule in 2020 ( Figure 1 ). Model outcomes for PCV13 and PCV15 reflect an overlap in projected IPD incidence for shared STCs, with a 14.6%-20.0% decline in the incidence of serotypes covered by both PCV13 and PCV15 over the 20-year time horizon following the switch to the reduced dosing schedule ( Figure 1a and 1b , Table 4 ). IPD incidence due to PCV15-unique STCs declined by 93.1% over the time horizon with implementation of PCV15 and increased by 6.3% with continued PCV13 vaccination ( Figure 1c and 1d , Table 4 ). IPD incidence due to serotypes not included in PCV13 increased by 10.3% and 23.0% ( Figure 1e and 1f ), and IPD incidence due to serotypes not included in PCV15 increased by 30.7% and 26.4% for PCV15 and PCV13 scenarios, respectively ( Figure 1g and 1h , Table 4 ). The absolute increase in overall IPD over the time horizon was smaller for PCV15 than for PCV13 (3.5% vs 11.1%) ( Figure 1i and 1j , Table 4 ). Sensitivity analyses reflect results were robust to potential changes in VE against IPD. Download figure Open in new tab Figure 1. 20-year projections of IPD incidence in <2-year-olds by serotype grouping. The two columns showcase the same results; the left column focuses on the projection period only while the right column includes the calibration period. The first three rows illustrate IPD by ST grouping and the fourth row illustrates overall IPD incidence in <2-year-olds. ST – Serotype. Population-level projections of IPD At the population level, projected overall IPD incidence outcomes for PCV13 and PCV15 overlapped for children aged 2-4-years-old over the duration of the 20-year time horizon ( Figure 2a and 2b ). Further, the model projected a 4.2% decrease in IPD incidence in the 2-4-year-old age group following the introduction of PCV15, compared with negligible change in IPD incidence for this same age group with implementation of PCV13 ( Table 5 ). The model projected a smaller increase in IPD incidence with the introduction of PCV15 when compared with PCV13 for the <2-(3.5% increase vs 11.2% increase, Table 4 ) and 5-64-year-old (5.1% increase vs 7.8% increase) age groups, as well as for the overall population (0.6% increase vs 7.1% increase, Figure 3 and Table 5 ). As seen with children <2 years of age, sensitivity analyses reflected projected IPD incidence results for all modeled age groups were robust to potential changes in VE against IPD. Download figure Open in new tab Figure 2. 20-year projections of IPD in 2-4-, 5-64-, and ≥65-year-olds. The two columns showcase the same results; the left column focuses on the projection period only while the right column includes the calibration period. Each row represents a different age group. Download figure Open in new tab Figure 3. 20-year projections of IPD in the entire population. The two columns showcase the same results; the left column focuses on the projection period only while the right column includes the calibration period. View this table: View inline View popup Download powerpoint Table 5. Projected IPD incidence (per 100,000) by age. IPD incidence at the start of the projection (0 years) and at the end of the 20-year time horizon, with administration of either PCV13 or PCV15 in the <2-year-old population. The mean projections of IPD, percent change from start of projections, and the 90% confidence intervals (5% and 95% quantiles) are included. DISCUSSION Despite the inclusion of effective PCVs in pediatric vaccination programs, residual pneumococcal disease remains a public health matter in the UK and throughout the world. Here, a previously described and calibrated dynamic transmission model was used to investigate the clinical outcomes resulting from potential reductions in VE with two PCVs (PCV13 and PCV15) when routinely administered in a reduced pediatric dosing schedule (1+1) in the UK. 10 , 11 Model projections predict the use of PCV15 would significantly reduce IPD incidence both in children <2 years of age, due to direct protection, and in older children and adults, due to indirect protection, with respect to continued use of PCV13. These effects were consistent regardless of potential changes in VE against disease. Reductions in IPD in children <2 years old attributed to the serotypes unique to PCV15 (22F and 33F) drove PCV15 to avert more disease than PCV13 in model projections. While both PCV13 and PCV15 led to projected decreases in IPD attributed to serotypes covered by both PCV13 and PCV15 in this age group, PCV15 led to a smaller projected decrease when compared with PCV13. Marginal increases in non-PCV15 serotypes were projected. Nevertheless, these differences were insufficient to counteract the overall estimated clinical benefits of pediatric PCV15 vaccination observed in the <2-year-old age group and in the population as a whole. With either vaccine, relative to current 2019 estimates of IPD incidence, overall IPD incidence was predicted to increase over the 20-year time horizon, though the projected overall increase was predicted to be smaller with implementation of PCV15 than with PCV13 vaccination. In contrast, a recent model by Choi et al evaluated the implications of introducing higher valency pediatric vaccines in the UK via the 1+1 schedule and concluded the introduction of PCV15 could result in increased IPD relative to the standard of care of PCV13. 7 These findings were in part a function of this study’s projection assumption on serotype replacement, wherein a decline in the carriage of a VT ST would be met with 100% replacement of carriage with a NVT ST, although this assumption is not substantiated by historical data to date. While it is necessary to make assumptions regarding the level of replacement expected upon the introduction of higher valency vaccines, assuming 100% replacement may lead to unreasonably high predictions of disease incidence of NVT STs. In contrast, the current analysis estimated competition between PCV13 and non-PCV13 STs through model calibration. However, there were insufficient data to estimate competition parameters between PCV15 and non-PCV15 STs, thus minimal competition between PCV15 and non-PCV15 STs was assumed. In addition, the Choi et al analysis implemented two separate calibration models for model fitting to historical data, which has the potential to introduce bias and confounding effects due to incompatibilities between the two models. 7 The current analysis employed a single model for calibration and fitting, to ensure compatibility and consistency. Several simplifying assumptions were made in the current analysis due to model complexity and limited availability of data. Potential reduction in VE against disease resulting from a change to a reduced pediatric vaccination schedule was considered, but there may also be reduced duration of protection and reduced VE against carriage. 6 Reductions in VE against carriage may lead to an increase in VT carriage, which could then increase VT-IPD in pediatric populations due to direct effects and adult populations due to indirect effects. In addition, consistent with previous modeling studies, 7 we did not consider the possibility of immunogenicity creep with the introduction of PCV15. This will be an important area of future research as real-world data become available for expanded valency PCVs. There were several limitations to this analysis. First, the model is very sensitive to estimates of calibrated parameters, including VE against carriage. Although this model considered a range of potential reductions in VE against disease that could occur resulting from a change to a reduced dosing schedule, it could not consider potential changes in VE against carriage without conducting a more in-depth parameter identifiability analysis. Second, the PSA only considered the VE against disease after the toddler dose (i.e., at the completion of the 1+1 dosing schedule). VE in the first year of life (i.e., the VE after receiving the single infant dose in the 1+1 schedule) may be more critical to evaluate given the vulnerability of infants to IPD. 5 However, since the model is not dose dependent, it could not explicitly predict the effects of two infant doses (in a 2+1 schedule) compared to a single infant dose (in a 1+1 schedule). Modeling dose dependent VEs and the potential for breakthrough IPD in infants with a reduced dosing schedule will be an important avenue for future research. Third, as there are limited data on real-world estimates of VEs against disease in a 1+1 dosing schedule, in part due to the COVID-19 pandemic coinciding with the start of the reduced dosing schedule in the UK, this PSA was instead informed by average changes when moving from a 3+1 to 2+1 dosing schedule. 22 As more estimates of VE against disease and carriage become available, it will be important to incorporate these into model-based predictions. Finally, to reduce computational load, this model stratified the population into four age groups, with the 5-64-year-old age group comprising the majority of the population. Since the model did not include restricted carriage transmission from adults to children, this age stratification may result in an under-estimation of disease among all age groups. Finally, future work should consider estimating the public health effects associated with other higher valency pediatric vaccines, including a 20-valent PCV (PCV20). CONCLUSIONS Switching from PCV13 to PCV15 for routine pediatric vaccination via the 1+1 dosing schedule in the UK would not only further reduce IPD in the pediatric population but would also lead to population-level reductions in IPD due to indirect protection. Although this model predicted short-term increases in VT-IPD associated with potential reductions in VE against disease in a reduced dosing schedule, the effects were not persistent into the future, and these transient increases were smaller in magnitude with the implementation of PCV15 than continued use of PCV13. In countries with lower pediatric VCRs, nascent pneumococcal vaccination programs, or uncontrolled VT-IPD, a reduced dosing schedule may lead to more pronounced and persistent increases in VT-IPD. Data Availability All relevant data are within the manuscript and its Supporting Information files. This is a modeling study and, therefore, no primary data was collected in this study. All inputs were from published literature and included only anonymized data. Disclosures RJO, NB, JW, TMM, and OS are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. IRM and DN are employees of MSD (UK) Ltd., London, United Kingdom. GM is an employee of Wolfram Research Inc. under contract to Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. JCL is an employee of Merck Canada, Inc., Kirkland, QC, Canada. RJO, NB, JW, IRM, DN, TMM, JCL, and OS may hold stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. Funding This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The funder provided support in the form of salaries or consulting fees for authors. SUPPLEMENTARY FIGURES / TABLES Download figure Open in new tab Figure S1. Model diagram. Upon carriage acquisition, individuals moved to either the colonized, co-colonized, or triple-colonized classes, depending on whether one or two serotypes were acquired (denoted in blue). Some portion of individuals from these colonized classes would develop a pneumococcal disease (denoted in red and orange). Recovery then moved individuals back to the non-colonized class (denoted in light green), sequentially clearing one serotype at a time. Vaccination (dark green border) reduced the risk of carriage acquisition and disease development for vaccine serotypes. Download figure Open in new tab Figure S2. Model calibration to historical observed IPD incidence per 100,000 population by ST grouping and age group. Comparison of data (solid line) to model fit (dotted line) during the calibration period faceted by age group and vaccination grouping. Download figure Open in new tab Figure S3. Model validation of calibrated model comparing data to model fit during the calibration period, by age group. Points denote annual and STC-specific incidence and are colored by vaccination grouping. Black line indicates a 1:1 line. Root mean squared error (RMSE) values were 1.47, 0.597, 0.312, and 1.29 for the <2-, 2-4-, 5-64-, and ≥65-year-old age groups. Across all age groups, the RMSE was 1.03. View this table: View inline View popup Download powerpoint Table S1. Vaccine efficacy against disease for the <2-year-old age group 22 for a 2+1 schedule. View this table: View inline View popup Download powerpoint Table S2. Vaccine efficacy against disease for the 2-4-year-old and 5-64-year-old risk group and ≥65-year-old population for PPSV23. 23 Note that given the lack of real-world evidence for vaccine effectiveness against disease for novel vaccine serotypes (STCs 6-10), we assumed equivalency with previous VTs in adult PCVs. View this table: View inline View popup Download powerpoint Table S3. PCV Coverage for the <2-year-old age group. 39 View this table: View inline View popup Download powerpoint Table S4. PPSV23 Coverage for the ≥65-year-old age group . Data were from 2005-2018. For 2019, we assumed the same coverage as 2018. 40 View this table: View inline View popup Download powerpoint Table S5. PPSV23 Coverage for the at-risk 2-4- and 5-64-year-old age group. These calculations assume that the VCR of clinical risk groups is 49.0% and that the proportion of the 2-64-year-old population that falls within a clinical risk group is 9.7%. 41 ACKNOWLEDGEMENTS We wish to thank UKHSA for providing seroprevalence data, and we wish to thank Kevin Bakker and Kenneth Klinker for their efforts in the development of the UK model adaptation. We also wish to thank Robert Nachbar for his useful comments and suggestions during model development and adaptation to the UK, and Colleen Burgess for her assistance in the preparation of this manuscript. REFERENCES 1. ↵ Bertran M , D’Aeth JC , Abdullahi F , et al. Invasive pneumococcal disease 3 years after introduction of a reduced 1+ 1 infant 13-valent pneumococcal conjugate vaccine immunisation schedule in England: a prospective national observational surveillance study . The Lancet Infectious Diseases . 2024 ; 24 ( 5 ): 546 – 556 . OpenUrl CrossRef PubMed 2. ↵ Goldblatt D , Southern J , Andrews NJ , et al. 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 controlled trial . The Lancet Infectious Diseases . 2018 ; 18 ( 2 ): 171 – 179 . OpenUrl CrossRef PubMed 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 . The Pediatric infectious disease journal . 2006 ; 25 ( 4 ): 312 – 319 . OpenUrl CrossRef PubMed Web of Science 4. ↵ Ladhani SN , Collins S , Djennad A , et al. Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study . Lancet Infect Dis . Apr 2018 ; 18 ( 4 ): 441 – 451 . doi: 10.1016/S1473-3099(18)30052-5 OpenUrl CrossRef PubMed 5. ↵ Choi YH , Andrews N , Miller E . Estimated impact of revising the 13-valent pneumococcal conjugate vaccine schedule from 2+ 1 to 1+ 1 in England and Wales: A modelling study . PLoS medicine . 2019 ; 16 ( 7 ): e1002845 . OpenUrl 6. ↵ Wasserman M , Lucas A , Jones D , et al. Dynamic transmission modelling to address infant pneumococcal conjugate vaccine schedule modifications in the UK . Epidemiology & Infection . 2018 ; 146 ( 14 ): 1797 – 1806 . OpenUrl 7. ↵ Choi YH , Bertran M , Litt DJ , Ladhani SN , Miller E . Potential impact of replacing the 13-valent pneumococcal conjugate vaccine with 15-valent or 20-valent pneumococcal conjugate vaccine in the 1+ 1 infant schedule in England: a modelling study . The Lancet Public Health . 2024 ; 9 ( 9 ): e654 – e663 . OpenUrl 8. ↵ Hu T , Weiss T , Bencina G , Owusu-Edusei K , Petigara T . Comprehensive value assessments for new pediatric pneumococcal conjugate vaccines . Taylor & Francis ; 2021 . p. 1083 – 1086 . 9. ↵ Yeh SH , Gurtman A , Hurley DC , et al. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers . Pediatrics . 2010 ; 126 ( 3 ): e493 – e505 . OpenUrl CrossRef PubMed Web of Science 10. ↵ Malik TM M , Bakker K , Oidtman RJ , et al. A dynamic transmission model for assessing the impact of pneumococcal vaccination . medRxiv . 2024 :2024.06. 11.24308671. 11. ↵ Oidtman RJ , Meleleo GJ , Sharomi O , et al. Modeling the epidemiological impact of different adult pneumococcal vaccination strategies in the United Kingdom . Infectious Diseases and Therapy . 2025 : 1 – 16 . 12. ↵ ONS . Office for National Statistics Conceptions in England and Wales . 2019 . 13. ↵ ONS . Single life year table - UK edition . 2020 . 14. ↵ Prem K , Cook AR , Jit M . Projecting social contact matrices in 152 countries using contact surveys and demographic data . PLoS Comput Biol . Sep 2017 ; 13 ( 9 ): e1005697 . doi: 10.1371/journal.pcbi.1005697 OpenUrl CrossRef PubMed 15. ↵ Althouse B , Hammitt L , Grant L , et al. Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities . Epidemiology & Infection . 2017 ; 145 ( 13 ): 2750 – 2758 . OpenUrl CrossRef 16. ↵ NMinimize , Wolfram Language function . Version Updated 2022 . 2003. https://reference.wolfram.com/language/ref/NMinimize.html 17. ↵ Cleary DW , Jones J , Gladstone RA , et al. Changes in serotype prevalence of Streptococcus pneumoniae in Southampton, UK between 2006 and 2018 . Scientific Reports . 2022 ; 12 ( 1 ): 13332 . OpenUrl PubMed 18. ↵ Hussain M , Melegaro A , Pebody RG , et al. A longitudinal household study of Streptococcus pneumoniae nasopharyngeal carriage in a UK setting . Epidemiology & Infection . 2005 ; 133 ( 5 ): 891 – 898 . OpenUrl CrossRef PubMed Web of Science 19. ↵ FDA . CAPVAXIVE™ (Pneumococcal 21-valent Conjugate Vaccine) Injection, for intramuscular use . Accessed 03/03/2025, 2025 . https://www.fda.gov/media/179426/download 20. ↵ Løchen A , Anderson R . Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations . Clinical Microbiology and Infection . 2020 ; 26 ( 1 ): 60 – 70 . OpenUrl PubMed 21. ↵ Moore CE , Paul J , Foster D , et al. Reduction of invasive pneumococcal disease 3 years after the introduction of the 13-valent conjugate vaccine in the Oxfordshire region of England . J Infect Dis. Oct 1 2014 ; 210 ( 7 ): 1001 – 11 . doi: 10.1093/infdis/jiu213 OpenUrl CrossRef PubMed 22. ↵ Savulescu C , Krizova P , Valentiner-Branth P , et al. Effectiveness of 10 and 13-valent pneumococcal conjugate vaccines against invasive pneumococcal disease in European children: SpIDnet observational multicentre study . Vaccine. Jun 23 2022 ; 40 ( 29 ): 3963 – 3974 . doi: 10.1016/j.vaccine.2022.05.011 OpenUrl CrossRef 23. ↵ Andrews NJ , Waight PA , George RC , Slack MP , Miller E . Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales . Vaccine. Nov 6 2012 ; 30 ( 48 ): 6802 – 8 . doi: 10.1016/j.vaccine.2012.09.019 OpenUrl CrossRef PubMed 24. ↵ Hill PC , Cheung YB , Akisanya A , et al. Nasopharyngeal carriage of Streptococcus pneumoniae in Gambian infants: a longitudinal study . Clin Infect Dis. Mar 15 2008 ; 46 ( 6 ): 807 – 14 . doi: 10.1086/528688 OpenUrl CrossRef PubMed Web of Science 25. Chaguza C , Senghore M , Bojang E , et al. Carriage Dynamics of Pneumococcal Serotypes in Naturally Colonized Infants in a Rural African Setting During the First Year of Life . Front Pediatr . 2021 ; 8 : 587730 . doi: 10.3389/fped.2020.587730 OpenUrl CrossRef 26. Abdullahi O , Karani A , Tigoi CC , et al. Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District , Kenya. J Infect Dis. Oct 1 2012 ; 206 ( 7 ): 1020 – 9 . doi: 10.1093/infdis/jis447 OpenUrl CrossRef PubMed 27. Abdullahi O , Karani A , Tigoi CC , et al. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya . PLoS One . 2012 ; 7 ( 2 ): e30787 . doi: 10.1371/journal.pone.0030787 OpenUrl CrossRef PubMed 28. Dube FS , Ramjith J , Gardner-Lubbe S , et al. Longitudinal characterization of nasopharyngeal colonization with Streptococcus pneumoniae in a South African birth cohort post 13-valent pneumococcal conjugate vaccine implementation . Sci Rep. Aug 21 2018 ; 8 ( 1 ): 12497 . doi: 10.1038/s41598-018-30345-5 OpenUrl CrossRef PubMed 29. Turner P , Turner C , Jankhot A , et al. A longitudinal study of Streptococcus pneumoniae carriage in a cohort of infants and their mothers on the Thailand-Myanmar border . PLoS One . 2012 ; 7 ( 5 ): e38271 . doi: 10.1371/journal.pone.0038271 OpenUrl CrossRef PubMed 30. Cauchemez S , Temime L , Valleron AJ , et al. S. pneumoniae transmission according to inclusion in conjugate vaccines: Bayesian analysis of a longitudinal follow-up in schools . BMC Infect Dis. Jan 30 2006 ; 6 : 14 . doi: 10.1186/1471-2334-6-14 OpenUrl CrossRef PubMed 31. Grivea IN , Priftis KN , Giotas A , et al. Dynamics of pneumococcal carriage among day-care center attendees during the transition from the 7-valent to the higher-valent pneumococcal conjugate vaccines in Greece . Vaccine. Nov 12 2014 ; 32 ( 48 ): 6513 – 20 . doi: 10.1016/j.vaccine.2014.09.016 OpenUrl CrossRef 32. Sleeman KL , Griffiths D , Shackley F , et al. Capsular serotype-specific attack rates and duration of carriage of Streptococcus pneumoniae in a population of children . J Infect Dis. Sep 1 2006 ; 194 ( 5 ): 682 – 8 . doi: 10.1086/505710 OpenUrl CrossRef PubMed Web of Science 33. Hogberg L , Ekdahl K , Sjostrom K , et al. Penicillin-resistant pneumococci in Sweden 1997-2003: increased multiresistance despite stable prevalence and decreased antibiotic use . Microb Drug Resist . Spring 2006 ; 12 ( 1 ): 16 – 22 . doi: 10.1089/mdr.2006.12.16 OpenUrl CrossRef PubMed Web of Science 34. Hogberg L , Geli P , Ringberg H , Melander E , Lipsitch M , Ekdahl K . Age- and serogroup-related differences in observed durations of nasopharyngeal carriage of penicillin-resistant pneumococci . J Clin Microbiol . Mar 2007 ; 45 ( 3 ): 948 – 52 . doi: 10.1128/JCM.01913-06 OpenUrl Abstract / FREE Full Text 35. Auranen K , Mehtala J , Tanskanen A , M SK . Between-strain competition in acquisition and clearance of pneumococcal carriage--epidemiologic evidence from a longitudinal study of day-care children . Am J Epidemiol. Jan 15 2009 ; 171 ( 2 ): 169 – 76 . doi: 10.1093/aje/kwp351 OpenUrl CrossRef PubMed Web of Science 36. ↵ Pessoa D , Hoti F , Syrjanen R , et al. Comparative analysis of Streptococcus pneumoniae transmission in Portuguese and Finnish day-care centres . BMC Infect Dis. Apr 18 2013 ; 13 : 180 . doi: 10.1186/1471-2334-13-180 OpenUrl CrossRef 37. ↵ Vaccine uptake guidance and the latest coverage data . https://www.gov.uk/government/collections/vaccine-uptake 38. ↵ Blower SM , Dowlatabadi H . Sensitivity and Uncertainty Analysis of Complex-Models of Disease Transmission - an Hiv Model, as an Example . Int Stat Rev . Aug 1994 ; 62 ( 2 ): 229 – 243 . doi : Doi 10.2307/1403510 OpenUrl CrossRef Web of Science 39. ↵ 39. Childhood Vaccination Coverage Statistics - England: Pneumococcal Conjugate Vaccine (PCV) ( 2022 ). 40. ↵ UKHSA . Pneumococcal Polysaccharide Vaccine (PPV) coverage report, England, April 2021 to March 2022 . 41. ↵ 41. Pneumococcal Polysaccharide Vaccine (PPV) coverage report, England , April 2021 to March 2022 ( 2024 ). View the discussion thread. Back to top Previous Next Posted March 20, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule Rachel J Oidtman , Natalie Banniettis , Jessica Weaver , Ian R Matthews , Dionysios Ntais , Giulio Meleleo , Tufail M Malik , John C Lang , Oluwaseun Sharomi medRxiv 2025.03.19.25324262; doi: https://doi.org/10.1101/2025.03.19.25324262 Share This Article: Copy Citation Tools Predicting the epidemiological effects in the United Kingdom of moving from PCV13 to PCV15 in the routine pediatric 1+1 vaccination schedule Rachel J Oidtman , Natalie Banniettis , Jessica Weaver , Ian R Matthews , Dionysios Ntais , Giulio Meleleo , Tufail M Malik , John C Lang , Oluwaseun Sharomi medRxiv 2025.03.19.25324262; doi: https://doi.org/10.1101/2025.03.19.25324262 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Epidemiology Subject Areas All Articles Addiction Medicine (566) Allergy and Immunology (863) Anesthesia (295) Cardiovascular Medicine (4408) Dentistry and Oral Medicine (443) Dermatology (379) Emergency Medicine (606) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1505) Epidemiology (15201) Forensic Medicine (30) Gastroenterology (1119) Genetic and Genomic Medicine (6568) Geriatric Medicine (666) Health Economics (994) Health Informatics (4508) Health Policy (1365) Health Systems and Quality Improvement (1606) Hematology (537) HIV/AIDS (1262) Infectious Diseases (except HIV/AIDS) (15901) Intensive Care and Critical Care Medicine (1103) Medical Education (619) Medical Ethics (144) Nephrology (665) Neurology (6571) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1139) Occupational and Environmental Health (954) Oncology (3319) Ophthalmology (967) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (662) Pediatrics (1686) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5419) Public and Global Health (9200) Radiology and Imaging (2190) Rehabilitation Medicine and Physical Therapy (1367) Respiratory Medicine (1191) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fe6693f1f3658d3',t:'MTc3OTIyODQxMA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();