Report from the World Health Organization's immunization and vaccines-related implementation research advisory committee (IVIR-AC) meeting, virtual gathering, 26 February-1 March 2024.

The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.

Modelling respiratory syncytial virus age-specific risk of hospitalisation in term and preterm infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infections in children worldwide. The highest incidence of severe disease is in the first 6 months of life, with infants born preterm at greatest risk for severe RSV infections. The licensure of new RSV therapeutics (a long-acting monoclonal antibody and a maternal vaccine) in Europe, USA, UK and most recently in Australia, has driven the need for strategic decision making on the implementation of RSV immunisation programs. Data driven approaches, considering the local RSV epidemiology, are critical to advise on the optimal use of these therapeutics for effective RSV control. METHODS: We developed a dynamic compartmental model of RSV transmission fitted to individually-linked population-based laboratory, perinatal and hospitalisation data for 2000-2012 from metropolitan Western Australia (WA), stratified by age and prior exposure. We account for the differential risk of RSV-hospitalisation in full-term and preterm infants (defined as < 37 weeks gestation). We formulated a function relating age, RSV exposure history, and preterm status to the risk of RSV-hospitalisation given infection. RESULTS: The age-to-risk function shows that risk of hospitalisation, given RSV infection, declines quickly in the first 12 months of life for all infants and is 2.6 times higher in preterm compared with term infants. The hospitalisation risk, given infection, declines to < 10% of the risk at birth by age 7 months for term infants and by 9 months for preterm infants. CONCLUSIONS: The dynamic model, using the age-to-risk function, characterises RSV epidemiology for metropolitan WA and can now be extended to predict the impact of prevention measures. The stratification of the model by preterm status will enable the comparative assessment of potential strategies in the extended model that target this RSV risk group relative to all-population approaches. Furthermore, the age-to-risk function developed in this work has wider relevance to the epidemiological characterisation of RSV.

Modelling the impact of hybrid immunity on future COVID-19 epidemic waves.

BACKGROUND: Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. METHODS: To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization Western Pacific Region. RESULTS: We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. CONCLUSIONS: Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.

Modeling the impact of COVID-19 nonpharmaceutical interventions on respiratory syncytial virus transmission in South Africa.

Background: The South African government employed various nonpharmaceutical interventions (NPIs) to reduce the spread of SARS-CoV-2. Surveillance data from South Africa indicates reduced circulation of respiratory syncytial virus (RSV) throughout the 2020-2021 seasons. Here, we use a mechanistic transmission model to project the rebound of RSV in the two subsequent seasons. Methods: We fit an age-structured epidemiological model to hospitalization data from national RSV surveillance in South Africa, allowing for time-varying reduction in RSV transmission during periods of COVID-19 circulation. We apply the model to project the rebound of RSV in the 2022 and 2023 seasons. Results: We projected an early and intense outbreak of RSV in April 2022, with an age shift to older infants (6-23 months old) experiencing a larger portion of severe disease burden than typical. In March 2022, government alerts were issued to prepare the hospital system for this potentially intense outbreak. We then assess the 2022 predictions and project the 2023 season. Model predictions for 2023 indicate that RSV activity has not fully returned to normal, with a projected early and moderately intense wave. We estimate that NPIs reduced RSV transmission between 15% and 50% during periods of COVID-19 circulation. Conclusions: A wide range of NPIs impacted the dynamics of the RSV outbreaks throughout 2020-2023 in regard to timing, magnitude, and age structure, with important implications in a low- and middle-income countries (LMICs) setting where RSV interventions remain limited. More efforts should focus on adapting RSV models to LMIC data to project the impact of upcoming medical interventions for this disease.

Long-term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: A modelling study.

BACKGROUND: Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity. METHODS AND FINDINGS: We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus. CONCLUSIONS: Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality.

Estimating long-term vaccine effectiveness against SARS-CoV-2 variants: a model-based approach.

With the ongoing evolution of the SARS-CoV-2 virus updated vaccines may be needed. We fitted a model linking immunity levels and protection to vaccine effectiveness data from England for three vaccines (Oxford/AstraZeneca AZD1222, Pfizer-BioNTech BNT162b2, Moderna mRNA-1273) and two variants (Delta, Omicron). Our model reproduces the observed sustained protection against hospitalisation and death from the Omicron variant over the first six months following dose 3 with the ancestral vaccines but projects a gradual waning to moderate protection after 1 year. Switching the fourth dose to a variant-matched vaccine against Omicron BA.1/2 is projected to prevent nearly twice as many hospitalisations and deaths over a 1-year period compared to administering the ancestral vaccine. This result is sensitive to the degree to which immunogenicity data can be used to predict vaccine effectiveness and uncertainty regarding the impact that infection-induced immunity (not captured here) may play in modifying future vaccine effectiveness.

Quantifying the effect of delaying the second COVID-19 vaccine dose in England: a mathematical modelling study.

BACKGROUND: The UK was the first country to start national COVID-19 vaccination programmes, initially administering doses 3 weeks apart. However, early evidence of high vaccine effectiveness after the first dose and the emergence of the SARS-CoV-2 alpha variant prompted the UK to extend the interval between doses to 12 weeks. In this study, we aimed to quantify the effect of delaying the second vaccine dose in England. METHODS: We used a previously described model of SARS-CoV-2 transmission, calibrated to COVID-19 surveillance data from England, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data, using a Bayesian evidence-synthesis framework. We modelled and compared the epidemic trajectory in the counterfactual scenario in which vaccine doses were administered 3 weeks apart against the real reported vaccine roll-out schedule of 12 weeks. We estimated and compared the resulting numbers of daily infections, hospital admissions, and deaths. In sensitivity analyses, we investigated scenarios spanning a range of vaccine effectiveness and waning assumptions. FINDINGS: In the period from Dec 8, 2020, to Sept 13, 2021, the number of individuals who received a first vaccine dose was higher under the 12-week strategy than the 3-week strategy. For this period, we estimated that delaying the interval between the first and second COVID-19 vaccine doses from 3 to 12 weeks averted a median (calculated as the median of the posterior sample) of 58 000 COVID-19 hospital admissions (291 000 cumulative hospitalisations [95% credible interval 275 000-319 000] under the 3-week strategy vs 233 000 [229 000-238 000] under the 12-week strategy) and 10 100 deaths (64 800 deaths [60 200-68 900] vs 54 700 [52 800-55 600]). Similarly, we estimated that the 3-week strategy would have resulted in more infections compared with the 12-week strategy. Across all sensitivity analyses the 3-week strategy resulted in a greater number of hospital admissions. In results by age group, the 12-week strategy led to more hospitalisations and deaths in older people in spring 2021, but fewer following the emergence of the delta variant during summer 2021. INTERPRETATION: England's delayed-second-dose vaccination strategy was informed by early real-world data on vaccine effectiveness in the context of limited vaccine supplies in a growing epidemic. Our study shows that rapidly providing partial (single-dose) vaccine-induced protection to a larger proportion of the population was successful in reducing the burden of COVID-19 hospitalisations and deaths overall. FUNDING: UK National Institute for Health Research; UK Medical Research Council; Community Jameel; Wellcome Trust; UK Foreign, Commonwealth and Development Office; Australian National Health and Medical Research Council; and EU.

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study.

BACKGROUND: A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. METHODS: We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence in children aged 2-10 years between 10% and 65%) and over two west Africa seasonality archetypes. FINDINGS: Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared with an age-based strategy, averting an additional 14 000-47 000 cases per 100 000 children aged 5 years and younger over 15 years, dependent on seasonality and transmission intensity. We predicted that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 42 000-67 000 cases per 100 000 children aged 5 years and younger over 15 years compared with SMC alone. Transmission season duration was a key determinant of intervention effect, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. INTERPRETATION: RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising the effect relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current rates of other interventions, and potential achievable RTS,S coverage. FUNDING: UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust, and The Royal society.

Global impact of the first year of COVID-19 vaccination: a mathematical modelling study.

BACKGROUND: The first COVID-19 vaccine outside a clinical trial setting was administered on Dec 8, 2020. To ensure global vaccine equity, vaccine targets were set by the COVID-19 Vaccines Global Access (COVAX) Facility and WHO. However, due to vaccine shortfalls, these targets were not achieved by the end of 2021. We aimed to quantify the global impact of the first year of COVID-19 vaccination programmes. METHODS: A mathematical model of COVID-19 transmission and vaccination was separately fit to reported COVID-19 mortality and all-cause excess mortality in 185 countries and territories. The impact of COVID-19 vaccination programmes was determined by estimating the additional lives lost if no vaccines had been distributed. We also estimated the additional deaths that would have been averted had the vaccination coverage targets of 20% set by COVAX and 40% set by WHO been achieved by the end of 2021. FINDINGS: Based on official reported COVID-19 deaths, we estimated that vaccinations prevented 14·4 million (95% credible interval [Crl] 13·7-15·9) deaths from COVID-19 in 185 countries and territories between Dec 8, 2020, and Dec 8, 2021. This estimate rose to 19·8 million (95% Crl 19·1-20·4) deaths from COVID-19 averted when we used excess deaths as an estimate of the true extent of the pandemic, representing a global reduction of 63% in total deaths (19·8 million of 31·4 million) during the first year of COVID-19 vaccination. In COVAX Advance Market Commitment countries, we estimated that 41% of excess mortality (7·4 million [95% Crl 6·8-7·7] of 17·9 million deaths) was averted. In low-income countries, we estimated that an additional 45% (95% CrI 42-49) of deaths could have been averted had the 20% vaccination coverage target set by COVAX been met by each country, and that an additional 111% (105-118) of deaths could have been averted had the 40% target set by WHO been met by each country by the end of 2021. INTERPRETATION: COVID-19 vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. However, inadequate access to vaccines in low-income countries has limited the impact in these settings, reinforcing the need for global vaccine equity and coverage. FUNDING: Schmidt Science Fellowship in partnership with the Rhodes Trust; WHO; UK Medical Research Council; Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation; National Institute for Health Research; and Community Jameel.

Modelling the impact of vaccine hesitancy in prolonging the need for Non-Pharmaceutical Interventions to control the COVID-19 pandemic.

Background: Vaccine hesitancy - a delay in acceptance or refusal of vaccines despite availability - has the potential to threaten the successful roll-out of SARS-CoV-2 vaccines globally. In this study, we aim to understand the likely impact of vaccine hesitancy on the control of the COVID-19 pandemic. Methods: We modelled the potential impact of vaccine hesitancy on the control of the pandemic and the relaxation of non-pharmaceutical interventions (NPIs) by combining an epidemiological model of SARS-CoV-2 transmission with data on vaccine hesitancy from population surveys. Results: Our simulations suggest that the mortality over a 2-year period could be up to 7.6 times higher in countries with high vaccine hesitancy compared to an ideal vaccination uptake if NPIs are relaxed. Alternatively, high vaccine hesitancy could prolong the need for NPIs to remain in place. Conclusions: While vaccination is an individual choice, vaccine-hesitant individuals have a substantial impact on the pandemic trajectory, which may challenge current efforts to control COVID-19. In order to prevent such outcomes, addressing vaccine hesitancy with behavioural interventions is an important priority in the control of the COVID-19 pandemic.

Developing a prediction model to estimate the true burden of respiratory syncytial virus (RSV) in hospitalised children in Western Australia.

Respiratory syncytial virus (RSV) is a leading cause of childhood morbidity, however there is no systematic testing in children hospitalised with respiratory symptoms. Therefore, current RSV incidence likely underestimates the true burden. We used probabilistically linked perinatal, hospital, and laboratory records of 321,825 children born in Western Australia (WA), 2000-2012. We generated a predictive model for RSV positivity in hospitalised children aged < 5 years. We applied the model to all hospitalisations in our population-based cohort to determine the true RSV incidence, and under-ascertainment fraction. The model's predictive performance was determined using cross-validated area under the receiver operating characteristic (AUROC) curve. From 321,825 hospitalisations, 37,784 were tested for RSV (22.8% positive). Predictors of RSV positivity included younger admission age, male sex, non-Aboriginal ethnicity, a diagnosis of bronchiolitis and longer hospital stay. Our model showed good predictive accuracy (AUROC: 0.87). The respective sensitivity, specificity, positive predictive value and negative predictive values were 58.4%, 92.2%, 68.6% and 88.3%. The predicted incidence rates of hospitalised RSV for children aged < 3 months was 43.7/1000 child-years (95% CI 42.1-45.4) compared with 31.7/1000 child-years (95% CI 30.3-33.1) from laboratory-confirmed RSV admissions. Findings from our study suggest that the true burden of RSV may be 30-57% higher than current estimates.

Optimizing social and economic activity while containing SARS-CoV-2 transmission using DAEDALUS.

To study the trade-off between economic, social and health outcomes in the management of a pandemic, DAEDALUS integrates a dynamic epidemiological model of SARS-CoV-2 transmission with a multi-sector economic model, reflecting sectoral heterogeneity in transmission and complex supply chains. The model identifies mitigation strategies that optimize economic production while constraining infections so that hospital capacity is not exceeded but allowing essential services, including much of the education sector, to remain active. The model differentiates closures by economic sector, keeping those sectors open that contribute little to transmission but much to economic output and those that produce essential services as intermediate or final consumption products. In an illustrative application to 63 sectors in the United Kingdom, the model achieves an economic gain of between £161 billion (24%) and £193 billion (29%) compared to a blanket lockdown of non-essential activities over six months. Although it has been designed for SARS-CoV-2, DAEDALUS is sufficiently flexible to be applicable to pandemics with different epidemiological characteristics.

Analysis of the potential for a malaria vaccine to reduce gaps in malaria intervention coverage.

BACKGROUND: The RTS,S/AS01 malaria vaccine is currently being evaluated in a cluster-randomized pilot implementation programme in three African countries. This study seeks to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions. METHODS: Using data from household surveys, the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit with Plasmodium falciparum parasite prevalence greater than 10% was calculated. Multilevel logistic regression was used to explore patterns of overlap by demographic and socioeconomic variables. The public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN), but who received the DTP3 vaccine, was also estimated. RESULTS: Uptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. It was estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert up to an estimated 9.7 million (range 8.5-10.8 million) clinical malaria cases each year, assuming all children who receive DTP3 are administered all four RTS,S doses. An additional 10.8 million (9.5-12.0 million) cases could be averted by vaccinating those 24 million children who receive the DTP3 vaccine and use an ITN. Children who had access to or used an ITN were 9-13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers' education status was a strong predictor of intervention uptake and was positively associated with use of ITNs and vaccination uptake and negatively associated with having access to an ITN but not using it. Wealth was also a strong predictor of intervention coverage. CONCLUSIONS: Childhood vaccination to prevent malaria has the potential to reduce inequity in access to existing malaria interventions and could substantially reduce the childhood malaria burden in sub-Saharan Africa, even in regions with lower existing DTP3 coverage.

Health inequities and clustering of fever, acute respiratory infection, diarrhoea and wasting in children under five in low- and middle-income countries: a Demographic and Health Surveys analysis.

BACKGROUND: Pneumonia, diarrhoea and malaria are responsible for over one third of all deaths in children under the age of 5 years in low and middle sociodemographic index countries; many of these deaths are also associated with malnutrition. We explore the co-occurrence and clustering of fever, acute respiratory infection, diarrhoea and wasting and their relationship with equity-relevant variables. METHODS: Multilevel, multivariate Bayesian logistic regression models were fitted to Demographic and Health Survey data from over 380,000 children in 39 countries. The relationship between outcome indicators (fever, acute respiratory infection, diarrhoea and wasting) and equity-relevant variables (wealth, access to health care and rurality) was examined. We quantified the geographical clustering and co-occurrence of conditions and a child's risk of multiple illnesses. RESULTS: The prevalence of outcomes was very heterogeneous within and between countries. There was marked spatial clustering of conditions and co-occurrence within children. For children in the poorest households and those reporting difficulties accessing healthcare, there were significant increases in the probability of at least one of the conditions in 18 of 21 countries, with estimated increases in the probability of up to 0.23 (95% CrI, 0.06-0.40). CONCLUSIONS: The prevalence of fever, acute respiratory infection, diarrhoea and wasting are associated with equity-relevant variables and cluster together. Via pathways of shared aetiology or risk, those children most disadvantaged disproportionately suffer from these conditions. This highlights the need for horizontal approaches, such as integrated community case management, with a focus on equity and targeted to those most at need.

A Systematic Review of the Costs Relating to Non-pharmaceutical Interventions Against Infectious Disease Outbreaks.

BACKGROUND: Non-pharmaceutical interventions (NPIs) are the cornerstone of infectious disease outbreak response in the absence of effective pharmaceutical interventions. Outbreak strategies often involve combinations of NPIs that may change according to disease prevalence and population response. Little is known with regard to how costly each NPI is to implement. This information is essential to inform policy decisions for outbreak response. OBJECTIVE: To address this gap in existing literature, we conducted a systematic review on outbreak costings and simulation studies related to a number of NPI strategies, including isolating infected individuals, contact tracing and quarantine, and school closures. METHODS: Our search covered the MEDLINE and EMBASE databases, studies published between 1990 and 24 March 2020 were included. We included studies containing cost data for our NPIs of interest in pandemic, epidemic, and outbreak response scenarios. RESULTS: We identified 61 relevant studies. There was substantial heterogeneity in the cost components recorded for NPIs in outbreak costing studies. The direct costs of NPIs for which costing studies existed also ranged widely: isolating infected individuals per case: US$141.18 to US$1042.68 (2020 values), tracing and quarantine of contacts per contact: US$40.73 to US$93.59, social distancing: US$33.76 to US$167.92, personal protection and hygiene: US$0.15 to US$895.60. CONCLUSION: While there are gaps and heterogeneity in available cost data, the findings of this review and the collated cost database serve as an important resource for evidence-based decision-making for estimating costs pertaining to NPI implementation in future outbreak response policies.

Modelling the impact of respiratory syncytial virus (RSV) vaccine and immunoprophylaxis strategies in New Zealand.

BACKGROUND: Mathematical models of respiratory syncytial virus (RSV) transmission can help describe seasonal epidemics and assess the impact of potential vaccines and immunoprophylaxis with monoclonal antibodies (mAb). METHODS: We developed a deterministic, compartmental model for RSV transmission, which was fitted to population-based RSV hospital surveillance data from Auckland, New Zealand. The model simulated the introduction of either a maternal vaccine or a seasonal mAb among infants aged less than 6 months and estimated the reduction in RSV hospitalizations for a range of effectiveness and coverage values. RESULTS: The model accurately reproduced the annual seasonality of RSV epidemics in Auckland. We found that a maternal vaccine with effectiveness of 30-40% in the first 90 days and 15-20% for the next 90 days could reduce RSV hospitalizations by 18-24% in children younger than 3 months, by 11-14% in children aged 3-5 months, and by 2-3% in children aged 6-23 months. A seasonal infant mAb with 40-60% effectiveness for 150 days could reduce RSV hospitalizations by 30-43%, 34-48% and by 14-21% in children aged 0-2 months, 3-5 months and 6-23 months, respectively. CONCLUSIONS: Our results suggest that either a maternal RSV vaccine or mAb would effectively reduce RSV hospitalization disease burden in New Zealand. Overall, a seasonal mAb resulted in a larger disease prevention impact than a maternal vaccine.

Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: A mathematical modelling analysis.

The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extend a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identify optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We find that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for < 20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: A modelling study.

BACKGROUND: The RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling. METHODS AND FINDINGS: Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0-5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels-assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%-we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8-6.8 million) and 22,000 deaths (95% CrI 11,000-35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million cases (95% CrI 2.0-4.7 million) and 14,000 deaths (95% CrI 7,000-23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2-10.8 million) and 38,000 deaths (95% CrI 18,000-61,000) at a dose constraint of 60 million. At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5-8.2 million) and 27,000 deaths (95% CrI 14,000-43,000), 3.9 million cases (95% CrI 2.7-6.0 million) and 19,000 deaths (95% CrI 10,000-30,000), and 10.0 million cases (95% CrI 6.7-15.7 million) and 51,000 deaths (95% CrI 25,000-82,000), respectively. Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5-8.2 million) and 24,000 deaths (95% CrI 12,000-38,000) could be averted at a dose constraint of 30 million. Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11). If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available. We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation. CONCLUSIONS: These results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence.

Modelling the household-level impact of a maternal respiratory syncytial virus (RSV) vaccine in a high-income setting.

BACKGROUND: Respiratory syncytial virus (RSV) infects almost all children by the age of 2 years, with the risk of hospitalisation highest in the first 6 months of life. Development and licensure of a vaccine to prevent severe RSV illness in infants is a public health priority. A recent phase 3 clinical trial estimated the efficacy of maternal vaccination at 39% over the first 90 days of life. Households play a key role in RSV transmission; however, few estimates of population-level RSV vaccine impact account for household structure. METHODS: We simulated RSV transmission within a stochastic, individual-based model framework, using an existing demographic model, structured by age and household and parameterised with Australian data, as an exemplar of a high-income country. We modelled vaccination by immunising pregnant women and explicitly linked the immune status of each mother-infant pair. We quantified the impact on children for a range of vaccine properties and uptake levels. RESULTS: We found that a maternal immunisation strategy would have the most substantial impact in infants younger than 3 months, reducing RSV infection incidence in this age group by 16.6% at 70% vaccination coverage. In children aged 3-6 months, RSV infection was reduced by 5.3%. Over the first 6 months of life, the incidence rate for infants born to unvaccinated mothers was 1.26 times that of infants born to vaccinated mothers. The impact in older age groups was more modest, with evidence of infections being delayed to the second year of life. CONCLUSIONS: Our findings show that while individual benefit from maternal RSV vaccination could be substantial, population-level reductions may be more modest. Vaccination impact was sensitive to the extent that vaccination prevented infection, highlighting the need for more vaccine trial data.