Report from the World Health Organization's immunization and vaccines related implementation research advisory committee (IVIR-AC) meeting, Geneva, 11-13 September 2023.

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates.

Modelling the Cost-Effectiveness of Hepatitis A in South Africa.

The World Health Organization (WHO) recommends the consideration of introducing routine hepatitis A vaccination into national immunization schedules for children ≥ 1 years old in countries with intermediate HAV endemicity. Recent data suggest that South Africa is transitioning from high to intermediate HAV endemicity, thus it is important to consider the impact and cost of potential routine hepatitis A vaccination strategies in the country. An age-structured compartmental model of hepatitis A transmission was calibrated with available data from South Africa, incorporating direct costs of hepatitis A treatment and vaccination. We used the calibrated model to evaluate the impact and costs of several childhood hepatitis A vaccination scenarios from 2023 to 2030. We assessed how each scenario impacted the burden of hepatitis A (symptomatic hepatitis A cases and mortality) as well as calculated the incremental cost per DALY averted as compared to the South African cost-effectiveness threshold. All costs and outcomes were discounted at 5%. For the modelled scenarios, the median estimated cost of the different vaccination strategies ranged from USD 1.71 billion to USD 2.85 billion over the period of 2023 to 2030, with the cost increasing for each successive scenario and approximately 39-52% of costs being due to vaccination. Scenario 1, which represented the administration of one dose of the hepatitis A vaccine in children < 2 years old, requires approximately 5.3 million vaccine doses over 2023-2030 and is projected to avert a total of 136,042 symptomatic cases [IQR: 88,842-221,483] and 31,106 [IQR: 22,975-36,742] deaths due to hepatitis A over the period of 2023 to 2030. The model projects that Scenario 1 would avert 8741 DALYs over the period of 2023 to 2030; however, it is not cost-effective against the South African cost-effectiveness threshold with an ICER per DALY averted of USD 21,006. While Scenario 3 and 4 included the administration of more vaccine doses and averted more symptomatic cases of hepatitis A, these scenarios were absolutely dominated owing to the population being infected before vaccination through the mass campaigns at older ages. The model was highly sensitive to variation of access to liver transplant in South Africa. When increasing the access to liver transplant to 100% for the baseline and Scenario 1, the ICER for Scenario 1 becomes cost-effective against the CET (ICER = USD 2425). Given these findings, we recommend further research is conducted to understand the access to liver transplants in South Africa and better estimate the cost of liver transplant care for hepatitis A patients. The modelling presented in this paper has been used to develop a user-friendly application for vaccine policy makers to further interrogate the model outcomes and consider the costs and benefits of introducing routine hepatitis A vaccination in South Africa.

Correction: Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.

[This corrects the article DOI: 10.1371/journal.pmed.1003793.].

The role of modelling and analytics in South African COVID-19 planning and budgeting.

BACKGROUND: The South African COVID-19 Modelling Consortium (SACMC) was established in late March 2020 to support planning and budgeting for COVID-19 related healthcare in South Africa. We developed several tools in response to the needs of decision makers in the different stages of the epidemic, allowing the South African government to plan several months ahead. METHODS: Our tools included epidemic projection models, several cost and budget impact models, and online dashboards to help government and the public visualise our projections, track case development and forecast hospital admissions. Information on new variants, including Delta and Omicron, were incorporated in real time to allow the shifting of scarce resources when necessary. RESULTS: Given the rapidly changing nature of the outbreak globally and in South Africa, the model projections were updated regularly. The updates reflected 1) the changing policy priorities over the course of the epidemic; 2) the availability of new data from South African data systems; and 3) the evolving response to COVID-19 in South Africa, such as changes in lockdown levels and ensuing mobility and contact rates, testing and contact tracing strategies and hospitalisation criteria. Insights into population behaviour required updates by incorporating notions of behavioural heterogeneity and behavioural responses to observed changes in mortality. We incorporated these aspects into developing scenarios for the third wave and developed additional methodology that allowed us to forecast required inpatient capacity. Finally, real-time analyses of the most important characteristics of the Omicron variant first identified in South Africa in November 2021 allowed us to advise policymakers early in the fourth wave that a relatively lower admission rate was likely. CONCLUSION: The SACMC's models, developed rapidly in an emergency setting and regularly updated with local data, supported national and provincial government to plan several months ahead, expand hospital capacity when needed, allocate budgets and procure additional resources where possible. Across four waves of COVID-19 cases, the SACMC continued to serve the planning needs of the government, tracking waves and supporting the national vaccine rollout.

Mobilizing resources with an investment case to mitigate cross-border malaria transmission and achieve malaria elimination in South Africa.

South Africa's effort to eliminate malaria is significantly challenged by a large number of imported malaria cases, especially from neighbouring Mozambique. The country has a funding gap to achieve its malaria elimination goals (prior to 2019) and is ineligible to receive a national allocation from the Global Fund. The findings of an IC were utilised to successfully mobilise resources for malaria elimination in South Africa in 2018. A five-step resource mobilisation strategy was implemented to highlight financing challenges and leverage the economic evidence from an IC for malaria elimination in South Africa. South Africa's malaria programme implements control and elimination activities in three malaria-endemic provinces (KwaZulu Natal, Limpopo, and Mpumalanga). Driven by the IC findings, the South African government took an unprecedented step and increased total domestic malaria financing by approximately 36%, from the 2018/19 to the 2019/20 financial years through the creation of a new conditional grant for malaria. The IC findings predicted that malaria control in southern Mozambique is a prerequisite to eliminate malaria in South Africa. Based on this, the South African government also allocated funding towards a co-financing mechanism to support malaria control efforts in southern Mozambique. The IC findings assisted the South African National Department of Health to make a convincing case to key government decision-makers to invest in national malaria elimination and maximise economic returns in the long run. The South African government is the first in Southern Africa to mobilise a significant increase in domestic malaria financing to address the financial sustainability of both national and regional malaria elimination efforts. Continued surveillance activities will be required to prevent the re-establishment of malaria transmission even after malaria elimination is achieved in South Africa. Information sharing and close collaboration with provincial and national government officials were key to the successful outcome.

Differential in-hospital mortality and intensive care treatment over time: Informing hospital pathways for modelling COVID-19 in South Africa.

There are limited published data within sub-Saharan Africa describing hospital pathways of COVID-19 patients hospitalized. These data are crucial for the parameterisation of epidemiological and cost models, and for planning purposes for the region. We evaluated COVID-19 hospital admissions from the South African national hospital surveillance system (DATCOV) during the first three COVID-19 waves between May 2020 and August 2021. We describe probabilities and admission into intensive care units (ICU), mechanical ventilation, death, and lengths of stay (LOS) in non-ICU and ICU care in public and private sectors. A log-binomial model was used to quantify mortality risk, ICU treatment and mechanical ventilation between time periods, adjusting for age, sex, comorbidity, health sector and province. There were 342,700 COVID-19-related hospital admissions during the study period. Risk of ICU admission was 16% lower during wave periods (adjusted risk ratio (aRR) 0.84 [0.82-0.86]) compared to between-wave periods. Mechanical ventilation was more likely during a wave overall (aRR 1.18 [1.13-1.23]), but patterns between waves were inconsistent, while mortality risk in non-ICU and ICU were 39% (aRR 1.39 [1.35-1.43]) and 31% (aRR 1.31 [1.27-1.36]) higher during a wave, compared to between-wave periods, respectively. If patients had had the same probability of death during waves vs between-wave periods, we estimated approximately 24% [19%-30%] of deaths (19,600 [15,200-24,000]) would not have occurred over the study period. LOS differed by age (older patients stayed longer), ward type (ICU stays were longer than non-ICU) and death/recovery outcome (time to death was shorter in non-ICU); however, LOS remained similar between time periods. Healthcare capacity constraints as inferred by wave period have a large impact on in-hospital mortality. It is crucial for modelling health systems strain and budgets to consider how input parameters related to hospitalisation change during and between waves, especially in settings with severely constrained resources.

The National COVID-19 Epi Model (NCEM): Estimating cases, admissions and deaths for the first wave of COVID-19 in South Africa.

In March 2020 the South African COVID-19 Modelling Consortium was formed to support government planning for COVID-19 cases and related healthcare. Models were developed jointly by local disease modelling groups to estimate cases, resource needs and deaths due to COVID-19. The National COVID-19 Epi Model (NCEM) while initially developed as a deterministic compartmental model of SARS-Cov-2 transmission in the nine provinces of South Africa, was adapted several times over the course of the first wave of infection in response to emerging local data and changing needs of government. By the end of the first wave, the NCEM had developed into a stochastic, spatially-explicit compartmental transmission model to estimate the total and reported incidence of COVID-19 across the 52 districts of South Africa. The model adopted a generalised Susceptible-Exposed-Infectious-Removed structure that accounted for the clinical profile of SARS-COV-2 (asymptomatic, mild, severe and critical cases) and avenues of treatment access (outpatient, and hospitalisation in non-ICU and ICU wards). Between end-March and early September 2020, the model was updated 11 times with four key releases to generate new sets of projections and scenario analyses to be shared with planners in the national and provincial Departments of Health, the National Treasury and other partners. Updates to model structure included finer spatial granularity, limited access to treatment, and the inclusion of behavioural heterogeneity in relation to the adoption of Public Health and Social Measures. These updates were made in response to local data and knowledge and the changing needs of the planners. The NCEM attempted to incorporate a high level of local data to contextualise the model appropriately to address South Africa's population and health system characteristics that played a vital role in producing and updating estimates of resource needs, demonstrating the importance of harnessing and developing local modelling capacity.

A retrospective study assessing the clinical outcomes and costs of acute hepatitis A in Cape Town, South Africa.

BACKGROUND: While some evidence has been demonstrated the cost-effectiveness of routine hepatitis A vaccination in middle-income countries, the evidence is still limited in other settings including in South Africa. Given this, the evidence base around the cost of care for hepatitis A needs to be developed towards considerations of introducing hepatitis A vaccines in the national immunisation schedule and guidelines. OBJECTIVES: To describe the severity, clinical outcomes, and cost of hepatitis A cases presenting to two tertiary healthcare centers in Cape Town, South Africa. METHODS: We conducted a retrospective folder review of patients presenting with hepatitis A at two tertiary level hospitals providing care for urban communities of metropolitan Cape Town, South Africa. Patients included in this folder review tested positive for hepatitis A immunoglobulin M between 1 January 2008 and 1 March 2018. RESULTS: In total, 239 folders of hepatitis A paediatric patients < 15 years old and 212 folders of hepatitis A adult patients [Formula: see text] 15 years old were included in the study. Before presenting for tertiary level care, more than half of patients presented for an initial consultation at either a community clinic or general physician. The mean length of hospital stay was 7.45 days for adult patients and 3.11 days for paediatric patients. Three adult patients in the study population died as a result of hepatitis A infection and 29 developed complicated hepatitis A. One paediatric patient in the study population died as a result of hepatitis A infection and 27 developed complicated hepatitis A, including 4 paediatric patients diagnosed with acute liver failure. The total cost per hepatitis A hospitalisation was $1935.41 for adult patients and $563.06 for paediatric patients, with overhead costs dictated by the length of stay being the largest cost driver. CONCLUSION: More than 1 in every 10 hepatitis A cases (13.3%) included in this study developed complicated hepatitis A or resulted in death. Given the severity of clinical outcomes and high costs associated with hepatitis A hospitalisation, it is important to consider the introduction of hepatitis A immunisation in the public sector in South Africa to potentially avert future morbidity, mortality, and healthcare spending.

Assessing the effectiveness of malaria interventions at the regional level in Ghana using a mathematical modelling application.

Supporting malaria control with interfaced applications of mathematical models that enables investigating effectiveness of various interventions as well as their cost implications could be useful. Through their usage for planning, these applications may improve the prospects of attaining various set targets such as those of the National Strategic Plan policies for malaria control in Ghana. A malaria model was adapted and used for simulating the incidence of malaria in various regions of Ghana. The model and its application were developed by the Modelling and Simulation Hub Africa and calibrated using district level data in Ghana from 2012 to 2018. Average monthly rainfall at the zonal level was fitted to trigonometric functions for each ecological zone using least squares approach. These zonal functions were then used as forcing functions. Subsequently, various intervention packages were investigated to observe their impact on averting malaria incidence by 2030. Increased usage of bednets but not only coverage levels, predicted a significant proportion of cases of malaria averted in all regions. Whereas, improvements in the health system by way of health seeking, testing and treatment predicted a decline in incidence largely in all regions. With an increased coverage of SMC, to include higher age groups, a modest proportion of cases could be averted in populations of the Guinea savannah. Indoor residual spraying could also benefit populations of the Transitional forest and Coastal savannah as its impact is significant in averting incidence. Enhancing bednet usage to at least a doubling of the current usage levels and deployed in combination with various interventions across regions predicted significant reductions, in malaria incidence. Regions of the Transitional forest and Coastal savannah could also benefit from a drastic decline in incidence following a gradual introduction of indoor residual spraying on a sustained basis.

Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.

BACKGROUND: The importance of infectious disease epidemic forecasting and prediction research is underscored by decades of communicable disease outbreaks, including COVID-19. Unlike other fields of medical research, such as clinical trials and systematic reviews, no reporting guidelines exist for reporting epidemic forecasting and prediction research despite their utility. We therefore developed the EPIFORGE checklist, a guideline for standardized reporting of epidemic forecasting research. METHODS AND FINDINGS: We developed this checklist using a best-practice process for development of reporting guidelines, involving a Delphi process and broad consultation with an international panel of infectious disease modelers and model end users. The objectives of these guidelines are to improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. The guidelines are not designed to advise scientists on how to perform epidemic forecasting and prediction research, but rather to serve as a standard for reporting critical methodological details of such studies. CONCLUSIONS: These guidelines have been submitted to the EQUATOR network, in addition to hosting by other dedicated webpages to facilitate feedback and journal endorsement.

Investment case for malaria elimination in South Africa: a financing model for resource mobilization to accelerate regional malaria elimination.

BACKGROUND: Malaria continues to be a public health problem in South Africa. While the disease is mainly confined to three of the nine provinces, most local transmissions occur because of importation of cases from neighbouring countries. The government of South Africa has reiterated its commitment to eliminate malaria within its borders. To support the achievement of this goal, this study presents a cost-benefit analysis of malaria elimination in South Africa through simulating different scenarios aimed at achieving malaria elimination within a 10-year period. METHODS: A dynamic mathematical transmission model was developed to estimate the costs and benefits of malaria elimination in South Africa between 2018 and 2030. The model simulated a range of malaria interventions and estimated their impact on the transmission of Plasmodium falciparum malaria between 2018 and 2030 in the three endemic provinces of Limpopo, Mpumalanga and KwaZulu-Natal. Local financial, economic, and epidemiological data were used to calibrate the transmission model. RESULTS: Based on the three primary simulated scenarios: Business as Usual, Accelerate and Source Reduction, the total economic burden was estimated as follows: for the Business as Usual scenario, the total economic burden of malaria in South Africa was R 3.69 billion (USD 223.3 million) over an 11-year period (2018-2029). The economic burden of malaria was estimated at R4.88 billion (USD 295.5 million) and R6.34 billion (~ USD 384 million) for the Accelerate and Source Reduction scenarios, respectively. Costs and benefits are presented in midyear 2020 values. Malaria elimination was predicted to occur in all three provinces if the Source Reduction strategy was adopted to help reduce malaria rates in southern Mozambique. This could be achieved by limiting annual local incidence in South Africa to less than 1 indigenous case with a prediction of this goal being achieved by the year 2026. CONCLUSIONS: Malaria elimination in South Africa is feasible and economically worthwhile with a guaranteed positive return on investment (ROI). Findings of this study show that through securing funding for the proposed malaria interventions in the endemic areas of South Africa and neighbouring Mozambique, national elimination could be within reach in an 8-year period.

Cost-effectiveness of Remdesivir and Dexamethasone for COVID-19 Treatment in South Africa.

BACKGROUND: Dexamethasone and remdesivir have the potential to reduce coronavirus disease 2019 (COVID)-related mortality or recovery time, but their cost-effectiveness in countries with limited intensive care resources is unknown. METHODS: We projected intensive care unit (ICU) needs and capacity from August 2020 to January 2021 using the South African National COVID-19 Epi Model. We assessed the cost-effectiveness of (1) administration of dexamethasone to ventilated patients and remdesivir to nonventilated patients, (2) dexamethasone alone to both nonventilated and ventilated patients, (3) remdesivir to nonventilated patients only, and (4) dexamethasone to ventilated patients only, all relative to a scenario of standard care. We estimated costs from the health care system perspective in 2020 US dollars, deaths averted, and the incremental cost-effectiveness ratios of each scenario. RESULTS: Remdesivir for nonventilated patients and dexamethasone for ventilated patients was estimated to result in 408 (uncertainty range, 229-1891) deaths averted (assuming no efficacy [uncertainty range, 0%-70%] of remdesivir) compared with standard care and to save $15 million. This result was driven by the efficacy of dexamethasone and the reduction of ICU-time required for patients treated with remdesivir. The scenario of dexamethasone alone for nonventilated and ventilated patients requires an additional $159 000 and averts 689 [uncertainty range, 330-1118] deaths, resulting in $231 per death averted, relative to standard care. CONCLUSIONS: The use of remdesivir for nonventilated patients and dexamethasone for ventilated patients is likely to be cost-saving compared with standard care by reducing ICU days. Further efforts to improve recovery time with remdesivir and dexamethasone in ICUs could save lives and costs in South Africa.

The Role of Remdesivir in South Africa: Preventing COVID-19 Deaths Through Increasing Intensive Care Unit Capacity.

Countries such as South Africa have limited intensive care unit (ICU) capacity to handle the expected number of patients with COVID-19 requiring ICU care. Remdesivir can prevent deaths in countries such as South Africa by decreasing the number of days people spend in ICU, therefore freeing up ICU bed capacity.

Operational research: A multidisciplinary approach for the management of infectious disease in a global context.

Infectious diseases, both established and emerging, impose a significant burden globally. Successful management of infectious diseases requires considerable effort and a multidisciplinary approach to tackle the complex web of interconnected biological, public health and economic systems. Through a wide range of problem-solving techniques and computational methods, operational research can strengthen health systems and support decision-making at all levels of disease control. From improved understanding of disease biology, intervention planning and implementation, assessing economic feasibility of new strategies, identifying opportunities for cost reductions in routine processes, and informing health policy, this paper highlights areas of opportunity for operational research to contribute to effective and efficient infectious disease management and improved health outcomes.

Accounting for regional transmission variability and the impact of malaria control interventions in Ghana: a population level mathematical modelling approach.

BACKGROUND: This paper investigates the impact of malaria preventive interventions in Ghana and the prospects of achieving programme goals using mathematical models based on regionally diverse climatic zones of the country. METHODS: Using data from the District Health Information Management System of the Ghana Health Service from 2008 to 2017, and historical intervention coverage levels, ordinary non-linear differential equations models were developed. These models incorporated transitions amongst various disease compartments for the three main ecological zones in Ghana. The Approximate Bayesian Computational sampling approach, with a distance based rejection criteria, was adopted for calibration. A leave-one-out approach was used to validate model parameters and the most sensitive parameters were evaluated using a multivariate regression analysis. The impact of insecticide-treated bed nets and their usage, and indoor residual spraying, as well as their protective efficacy on the incidence of malaria, was simulated at various levels of coverage and protective effectiveness in each ecological zone to investigate the prospects of achieving goals of the Ghana malaria control strategy for 2014-2020. RESULTS: Increasing the coverage levels of both long-lasting insecticide-treated bed nets and indoor residual spraying activities, without a corresponding increase in their recommended utilization, does not impact highly on averting predicted incidence of malaria. Improving proper usage of long-lasting insecticide-treated bed nets could lead to substantial reductions in the predicted incidence of malaria. Similar results were obtained with indoor residual spraying across all ecological zones of Ghana. CONCLUSIONS: Projected goals set in the national strategic plan for malaria control 2014-2020, as well as World Health Organization targets for malaria pre-elimination by 2030, are only likely to be achieved if a substantial improvement in treated bed net usage is achieved, coupled with targeted deployment of indoor residual spraying with high community acceptability and efficacy.

Characterisation of the environmental presence of hepatitis A virus in low-income and middle-income countries: a systematic review and meta-analysis.

OBJECTIVE: To characterise the environmental presence of hepatitis A virus (HAV) in low- and middle-income countries (LMICs). DESIGN: Systematic review and meta-analysis. DATA SOURCES: EBSCOhost, PubMed, Scopus, ScienceDirect, Clinical Key and Web of Science were searched. Grey literature was sourced by searching the following electronic databases: Open Grey, National Health Research Database and Mednar. ELIGIBILITY CRITERIA FOR INCLUDING STUDIES: Cross-sectional and ecological studies reporting HAV environmental presence and conducted in LMICs between January 2005 and May 2019, irrespective of language of publication. DATA EXTRACTION AND DATA SYNTHESIS: Relevant data were extracted from articles meeting the inclusion criteria, and two reviewers independently assessed the studies for risk of bias. High heterogeneity of the extracted data led to the results being reported narratively. RESULTS: A total of 2092 records were retrieved, of which 33 met the inclusion criteria. 21 studies were conducted in Tunisia, India and South Africa, and the rest were from Philippines, Pakistan, Morocco, Chad, Mozambique, Kenya and Uganda. In Tunisian raw sewage samples, the prevalence of HAV ranged from 12% to 68%, with an estimated average detection rate of 50% (95% CI 25 to 75), whereas HAV detection in treated sewage in Tunisia ranged from 23% to 65%, with an estimated average detection rate of 38% (95% CI 20 to 57). The prevalence of HAV detection in South African treated sewage and surface water samples ranged from 4% to 37% and from 16% to 76%, with an estimated average detection rates of 15% (95% CI 1 to 29) and 51% (95% CI 21 to 80), respectively. Over the review period, the estimated average detection rate of environmental HAV presence appeared to have declined by 10%. CONCLUSION: The quality of included studies was fair, but sampling issues and paucity of data limited the strength of the review findings. PROSPERO REGISTRATION NUMBER: CRD42019119592.

Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.

Background South Africa recently experienced a first peak in COVID-19 cases and mortality. Dexamethasone and remdesivir both have the potential to reduce COVID-related mortality, but their cost-effectiveness in a resource-limited setting with scant intensive care resources is unknown. Methods We projected intensive care unit (ICU) needs and capacity from August 2020 to January 2021 using the South African National COVID-19 Epi Model. We assessed cost-effectiveness of 1) administration of dexamethasone to ventilated patients and remdesivir to non-ventilated patients, 2) dexamethasone alone to both non-ventilated and ventilated patients, 3) remdesivir to non-ventilated patients only, and 4) dexamethasone to ventilated patients only; all relative to a scenario of standard care. We estimated costs from the healthcare system perspective in 2020 USD, deaths averted, and the incremental cost effectiveness ratios of each scenario. Results Remdesivir for non-ventilated patients and dexamethasone for ventilated patients was estimated to result in 1,111 deaths averted (assuming a 0-30% efficacy of remdesivir) compared to standard care, and save $11.5 million. The result was driven by the efficacy of the drugs, and the reduction of ICU-time required for patients treated with remdesivir. The scenario of dexamethasone alone to ventilated and non-ventilated patients requires additional $159,000 and averts 1,146 deaths, resulting in $139 per death averted, relative to standard care. Conclusions The use of dexamethasone for ventilated and remdesivir for non-ventilated patients is likely to be cost-saving compared to standard care. Given the economic and health benefits of both drugs, efforts to ensure access to these medications is paramount.