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Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness [1]

['Simon R. Procter', 'Department Of Infectious Disease Epidemiology', 'London School Of Hygiene', 'Tropical Medicine', 'London', 'United Kingdom', 'Maternal', 'Adolescent', 'Reproductive', 'Child Health']

Date: 2023-04

Abstract Background Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally. Methods and findings We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low−/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($−0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts. Conclusions In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention.

Author summary Why was this study done? Group B Streprococcus (GBS) is a common bacterial pathogen that can infect pregnant women and their babies.

A recent global disease burden study showed that GBS infection causes a considerable burden of sepsis and meningitis in newborns, which can sometimes result in death or long-term disability, and it may also be linked to increased risk of stillbirth and preterm births.

Several vaccines against GBS for use during pregnancy are being developed.

A global economic evaluation of GBS vaccines is needed to inform investment decisions in vaccine development and to guide fair financing and pricing to enable equitable access once licensed vaccines become available. What did the researchers do and find? We developed a decision model to assess the cost-effectiveness of GBS vaccines in pregnant women in 183 countries for the year 2020.

Our model used the most recent global estimates of the health burden of GBS in pregnant women and their children together with estimated costs to healthcare systems.

We found that, globally, a maternal GBS vaccination programme, integrated in antenatal care, would lead to an overall increase in costs that are partially offset by savings in healthcare costs, along with substantial health gains, notably reductions in morbidity and mortality.

Globally, the value of the annual GBS vaccine programme ranged from $1.1 billion (95% uncertainty range: $−0.2 to 3.8 billion) to $17 billion ($9.1 to 31 billion) depending on the normative assumptions used by policymakers. What do these findings mean? Globally, GBS maternal immunisation is likely to be cost-effective and avert a substantial burden of death and disability in children.

At a regional and country level, cost-effectiveness is sensitive to vaccine prices and to different choices policymakers may use to value benefits in improved health.

Our findings highlight the need both for carefully tiered vaccine pricing to ensure equitable access across countries and for local assessment of cost-effectiveness as GBS vaccine moves towards licensure.

There is a need for more evidence on the impact of GBS on several outcomes, including stillbirths, preterm births, and maternal morbidity, as well as the wider societal costs of long-term GBS-related disability.

Citation: Procter SR, Gonçalves BP, Paul P, Chandna J, Seedat F, Koukounari A, et al. (2023) Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness. PLoS Med 20(3): e1004068. https://doi.org/10.1371/journal.pmed.1004068 Received: July 7, 2022; Accepted: February 7, 2023; Published: March 14, 2023 Copyright: © 2023 Procter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: Code and data used in this analysis are available at https://github.com/mert0248/GBS-vax-econ-model. Funding: SRP, BPG, PP, JC, FS, AK, JEL and MJ were supported by funding from a grant (INV-009018) to the London School of Hygiene & Tropical Medicine (PI JEL) from the Bill & Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FS is employed by the UK NSC which developed the policy recommendation for maternal GBS screening. RH is member of the World Health Organisation. Abbreviations: ANC, antenatal care; CET, cost-effectiveness threshold; CFR, case fatality risk; EOGBS, early-onset GBS; FVVA, Full Value of Vaccines Assessment; GBS, Group B Streptococcus; GDP, Gross Domestic Product; HRQoL, health-related quality of life; IAP, intrapartum antibiotic prophylaxis; ICER, incremental cost-effectiveness ratio; iGBS, invasive GBS; LOGBS, late-onset GBS; NDI, neurodevelopmental impairment; NMB, net monetary benefit; PDVAC, Product Development for Vaccines Advisory Committee; PPC, preferred product characteristic; QALY, quality-adjusted life year; SDG, Sustainable Development Goal; UNWPP, United Nations World Populations Prospects; UR, uncertainty range; USD, United States Dollars; VE, vaccine efficacy

Introduction Streptococcus agalactiae, commonly known as Group B Streptococcus (GBS), is an important bacterial pathogen causing morbidity and mortality in pregnant women and their babies and is also increasingly recognised as a cause of disease in nonpregnant adults [1–3]. Invasive GBS (iGBS) disease in neonates and young infants can result from maternal colonisation and vertical transmission or environmental exposure after birth. It is classified by age at onset with early-onset GBS (EOGBS), occurring in the first 6 days of life, and late-onset disease (LOGBS), occurring between ages 7 and 89 days, and typically presents as sepsis, meningitis, or pneumonia. In 2020, an estimated 20 million pregnant women globally were colonised with GBS resulting in 231,000 (114,000 to 455,000) cases of EOGBS and a further 162,000 (70,000 to 394,000) LOGBS cases [1]. Together, these were estimated to have caused 58,000 to 91,000 infant deaths depending on the assumptions made about mortality in cases without access to healthcare. Furthermore, survivors of iGBS are at risk of long-term neurological sequelae with an estimated 37,000 (14,000 to 96,000) surviving infants developing moderate or severe neurodevelopmental impairment (NDI) [1,4]. Maternal colonisation with GBS is also an important cause of adverse pregnancy outcomes with an estimated 46,000 (20,000 to 111,000) GBS stillbirths and is potentially linked with 518,000 (36,000 to 1,142,000) excess preterm births. Currently, the main strategies for preventing iGBS are based on intrapartum antibiotic prophylaxis (IAP). Many higher-income countries have reduced EOGBS incidence through IAP with eligible pregnant women identified either through risk factor–based screening or routine testing based on microbiological culture [5]. Despite this success, IAP has several limitations; notably, it is not effective against LOGBS- or GBS-associated stillbirths. In addition, the need for access to laboratory testing for microbiological screening–based strategies and the requirement to deliver antibiotics intravenously substantially limits the prospect of attaining high IAP coverage in many low-resource settings where the burden of iGBS is highest [5]. There are also concerns that routine administration of antibiotics could contribute to antimicrobial resistance and might also have unintended impacts on the gut microbiota of newborns [6]. Hence, there is substantial interest in alternative approaches to prevention. Maternal immunisation is a potential alternative strategy whereby vertical transfer of antibodies in utero from a woman vaccinated during pregnancy affords protection to the mother, unborn foetus, and newborn infant [7]. Maternal immunisation with Tetanus Toxoid has been successfully used to reduce the burden of neonatal tetanus since the 1970s, and, in the last decade, countries have been increasingly recommending routine vaccination of pregnant women against influenza and pertussis [8]. In 2015, development of a maternal vaccine against GBS was identified as a priority by the WHO Product Development for Vaccines Advisory Committee (PDVAC) [9], and 3 GBS maternal vaccine candidates have progressed to Phase II clinical trials [10]. In 2021, the licensure of an affordable GBS vaccine by 2026 was identified as a key milestone in the WHO global roadmap for Defeating Meningitis by 2030 [11]. There have been previous economic evaluations of maternal GBS vaccination in the United States [12–14], Europe [15–17], and sub-Saharan Africa [18–20]. However, none of these studies have estimated the value of GBS vaccination in all world regions. A global economic evaluation of GBS vaccination is important to drive investment into vaccine development by indicating the vaccine’s potential value in different markets. It would also enable financing and pricing mechanisms to be put in place for equitable access to the vaccine once it is available. Such an evaluation is central to a Full Value of Vaccines Assessment (FVVA), which WHO has identified as key to catalysing vaccine development and subsequent equitable access [21,22]. To inform the WHO GBS vaccine FVVA [23], we conducted the first global economic evaluation of maternal GBS vaccination in 183 countries, drawing on recently updated global disease burden estimates for GBS [1].

Discussion A high-coverage global maternal immunisation programme against GBS could avert hundreds of thousands of GBS cases, alongside tens of thousands of deaths, stillbirths, and cases of long-term disability. We estimate that such a programme may have a net cost of around $1.3 billion, with most costs occurring in Europe and Northern America. Nevertheless, it would be cost-effective in most countries under favourable assumptions, particularly if it can reduce preterm births. Even under less favourable assumptions, a single-dose GBS vaccine could still be cost-effective due to additional factors we did not explore. In some high-income countries, GBS vaccination plus current practice may be less cost-effective compared to current practice alone because of lower GBS incidence in babies due to IAP. However, GBS vaccination might allow high-income countries to achieve additional cost savings by revising IAP algorithms for vaccinated mothers. In low- and lower-middle-income countries, iGBS incidence may be higher, but so is the health opportunity cost of healthcare spending due to budget constraints leading to lower thresholds at which interventions may be considered cost-effective. More competitive pricing may enable vaccination to be cost-effective, even under least favourable assumptions. Competitive and finely tiered vaccine prices could also be beneficial for manufacturers, with financial analyses suggesting that high global demand is needed to ensure the development costs of a GBS vaccine can be recouped [46]. Our economic evaluation can inform both manufacturers and donors investigating the financial viability of investing in GBS vaccine development, as well as countries identifying the price they should be willing to pay for such a vaccine. To our knowledge, our study is the first to estimate the value of maternal GBS vaccination across all regions and country income groups. Previous analyses have estimated cost-effectiveness in the US [12–14], the Netherlands [17], UK [15,16], South Africa [19], The Gambia [18], and 37 Gavi countries in Africa [20]. These prior estimates suggested cost-effectiveness of vaccination ranged from $320 to 573 per DALY averted in Gavi-eligible countries [20], to $3,550 per DALY averted in South Africa [19], to over $50,000 per QALY in the US [12,13], which is broadly consistent with our results. Like our analysis, Kim and colleagues also found that the ability to avert GBS-associated prematurity greatly improved vaccine cost-effectiveness [19]. As far as we know, this was the first cost-effectiveness study to use new global estimates of the health burden due to GBS including infant morbidity and mortality, long-term NDI, stillbirth, and GBS-associated prematurity. This burden study propagated parametric uncertainty comprehensively by using a Bayesian framework to synthesise existing data sources. Posterior distributions from the study then informed a probabilistic sensitivity analysis for our cost-effectiveness model. Similarly, for cost data, parameters with multiple sources of data from previous systematic reviews were synthesised using regression models. Conversely, the main limitations of our analysis reflected parameters with limited data such as those governing health-related quality of life and long-term costs from disability, where estimates were based on only 1 to 2 relevant studies. Our analysis also excluded the potential impact of vaccination on maternal morbidity and the costs of GBS-related disability beyond the health-sector. However, both these factors would likely reinforce our main findings on cost-effectiveness. A further set of uncertainties govern GBS vaccine characteristics such as efficacy, number of doses needed, and impact on GBS-associated prematurity. Since there is currently no licensed vaccine, these parameters were informed by the WHO PPC, which is based on expert assumptions. We therefore used scenario sensitivity analyses to identify which of these characteristics are the most important drivers of vaccine value. Further data from carefully designed vaccine trials and other field studies are needed to inform these data gaps. Vaccine value is also driven by normative health economic assumptions around discounting, CETs, and the value of preventing stillbirths, which reflect uncertainty about the values of society rather than about empirical data. As GBS vaccines progress towards licensure, and new data on vaccine characteristics and GBS epidemiology become available, updated analyses tailored to individual country contexts can help ensure that vaccines are acquired at prices that are cost-effective. Overall, our results suggest high coverage of a competitively priced maternal GBS vaccine has the potential to save tens of thousands of lives globally and is likely to be a cost-effective investment, particularly if the vaccine can reduce GBS-associated prematurity.

Supporting information S1 Appendix. Supplementary appendix. Table A. Updated Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist from [53]. Table B. Model parameter values used in base case analysis. (a) For parameters estimated in our previously published burden model, we used samples of the posterior distribution of the parameter estimates, and these samples along with other model input data are provided online. Values presented in this table correspond to the mean of the posterior distributions. (b) Regions for these parameters are based on a country’s World Bank income classification. (c) See section A2.7. (d) See section A2.6. (e) For these parameters, countries are assigned to the “developed” region according to the World Bank development status; for countries not classified as “developed,” the region is based on the UN geographical region. (f) Regions for these parameters are based on a country’s World Bank development status. (g) In the base case, we conservatively assume no excess risk of mild NDI following GBS by setting the value for these parameters to the match the baseline risk of mild NDI, i.e., we assume Risk mild-NDI-sep = Risk mild-NDI-men = Risk mild-NDI-baseline . EOGBS, early-onset GBS; GBS, Group B Streptococcus; HIC, high-income country; iGBS, invasive GBS; LIC, low-income country; LMIC, lower middle-income country; LOGBS, late-onset GBS; NDI, neurodevelopmental impairment; OR, odds ratio; UMIC, upper middle-income country. Table C. Country-specific model inputs values. (a) Estimated using regression model (see section A2.6 for further details). (b) Estimated using regression model (see section A2.7 for further details). (c) Values in italics were based on the average across other high-income countries. (d) See section A2.5 for further details on how these values were estimated. (e) Based on estimates World Bank where available, otherwise based on estimated from the IMF. (f) Based on values from Ochalek and colleagues and Woods and colleagues—see section A2.8 for how these values were calculated; values in italics were imputed using regression against GDP per capita. ANC, antenatal care; CET, cost-effectiveness threshold; EOGBS, early-onset Group B Streptococcus disease; GDP, Gross Domestic Product; USD, United States Dollars. Table D. Changes to base case parameter assumptions used in scenario analysis. Table E. Distribution of preterm births by gestational age. The proportion of preterm births occurring by week of gestational age is based on the global values reported by Blencowe and colleagues [54] Table F. Country-specific estimates of the proportion of pregnant women vaccinated by gestation age in weeks. These estimates were provided by the authors of [39] and were calculated using input data on antenatal coverage that was available at the time of their analysis. Table G. Cost data used to extrapolate country-specific estimates of the acute healthcare costs of the iGBS episode. Table H. Cost data from [31] used to extrapolate used to extrapolate country-specific estimates of vaccine delivery costs per dose. Table I. Annual global and regional incremental impact of GBS vaccination compared with no vaccination for 2020 under high-coverage scenario. Fig A. Regional NMB of GBS vaccination under different normative assumptions about the discount rate for QALYs, the cost-effectiveness threshold, and whether the value of QALYs for averted stillbirths are included. M, Millions; B, Billions; CET, cost-effectiveness threshold; GDP, Gross Domestic Product; GDPPC, GDP per capita; NMB, net monetary benefit; QALY, quality-adjusted life year; SB, stillbirth; SDG, Sustainable Development Goal. Fig B. Regional NMB of different GBS maternal vaccination scenarios under the most and least favourable normative assumptions. Least favourable normative assumptions were the use of an empirical CET, 3% discounting of QALYs, and exclusion of stillbirth QALYs. Most favourable assumptions were the use of 1 × GDP per capita CETs, 0% discounting of QALYs, and inclusion of stillbirth QALYs. M, Millions; B, Billions; CET, cost-effectiveness threshold; GDP, Gross Domestic Product; GDPPC, GDP per capita; NMB, net monetary benefit; QALY, quality-adjusted life year; SB, stillbirth; SDG, Sustainable Development Goal. Fig C. Probability that GBS maternal vaccination is cost-effective in each country for base case vaccination scenario and different normative assumptions about the discount rate for QALYs, the cost-effectiveness threshold, and whether the value of QALYs for averted stillbirths are included. M, Millions; B, Billions; CET, cost-effectiveness threshold; GBS, Group B Streptococcus; GDP, Gross Domestic Product; GDPPC, GDP per capita; QALY, quality-adjusted life year; SB, stillbirth; SDG, Sustainable Development Goal. Fig D. Probability that GBS maternal vaccination is cost-effective in each country for different vaccination scenarios under most favourable and least favourable normative assumptions. Least favourable normative assumptions were the use of an empirical CET, 3% discounting of QALYs, and exclusion of stillbirth QALYs. Most favourable assumptions were the use of 1 × GDP per capita CETs, 0% discounting of QALYs, and inclusion of stillbirth QALYs. CET, cost-effectiveness threshold; GBS, Group B Streptococcus; GDP, Gross Domestic Product; GDPPC, GDP per capita; QALY, quality-adjusted life year; SB, stillbirth; SDG, Sustainable Development Goal. Fig E. Distribution of GBS vaccine threshold prices among countries within each SDG region under most and least favourable normative assumptions Threshold vaccine prices above $800 per dose are not shown. Fig F. Distribution of GBS vaccine threshold prices among countries within each World Bank region under most and least favourable normative assumptions for different vaccination scenarios. Threshold vaccine prices above $800 per dose are not shown. Least favourable normative assumptions were the use of an empirical CET, 3% discounting of QALYs, and exclusion of stillbirth QALYs. Most favourable assumptions were the use of 1 × GDP per capita CETs, 0% discounting of QALYs, and inclusion of stillbirth QALYs. B, Billions; CET, cost-effectiveness threshold; CFR, case fatality risk; GDP, Gross Domestic Product; NDI, neurodevelopmental impairment; SBA, skilled birth attendant; QALY, quality-adjusted life year; VE, vaccine effectiveness. Fig G. Tornado diagram showing impact of varying individual model parameters on the estimated global NMB using the least favourable normative assumptions. Only the top 100 most influential parameters are shown. The impact of varying each parameter value between the 2.5% and 97.5% quantiles (shown by the different colour bars) was estimated using multivariables linear regression. Regional parameters are shown by the region name in parentheses, country-level parameters by a suffix with the country iso3 code, and all other parameters are global. For the regression, the risk of maternal colonisation and risk of EOGBS given colonisation were combined into a single risk of EOGBS parameter for each country to preserve the correlation between these 2 jointly sampled parameters. Least favourable normative assumptions were the use of an empirical CET, 3% discounting of QALYs, and exclusion of stillbirth QALYs. CET, cost-effectiveness threshold; EOGBS, early-onset GBS disease; LOGBS, late-onset GBS disease; NDI, neurodevelopmental impairment. https://doi.org/10.1371/journal.pmed.1004068.s001 (DOCX)

Acknowledgments We would like to thank the authors of the GBS burden paper for sharing data on the posterior estimates of parameters in the burden model. We thank the GBS Full Value of Vaccine Assessment project Scientific Advisory Group for helpful discussion. We also thank Clint Pecenka and Ranju Baral for sharing estimates of antenatal care coverage by gestational age. The views expressed in this article are those of the authors and do not necessarily represent the decisions, official policy, or opinions of WHO.

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