Literature Review - the vaccine supply chain

Vaccination is one of the most effective ways to prevent the outbreak of an infectious disease. This medical intervention also brings about many logistical quest

Literature review: The vaccine supply chain

Vaccination is one of the most effective ways to prevent and/or control the outbreak of infectious diseases. This medical intervention also brings about many logistical questions. In the past years, the Operations Research/Operations Management community has shown a growing interest in the logistical aspects of vaccination. However, publications on vaccine logistics often focus on one specific logistical aspect. A broader framework is needed so that open research questions can be identified more easily and contributions are not overlooked.In this literature review, we combine the priorities of the World Health Organization for creating a flexible and robust vaccine supply chain with an Operations Research/Operations Management supply chain perspective. We propose a classification for the literature on vaccine logistics to structure this relatively new field, and identify promising research directions. We classify the literature into the following four components: (1) product, (2) production, (3) allocation, and (4) distribution. Within the supply chain classification, we analyze the decision problems for existing outbreaks versus sudden outbreaks and developing countries versus developed countries. We identify unique characteristics of the vaccine supply chain: high uncertainty in both supply and demand; misalignment of objectives and decentralized decision making between supplier, public health organization and end customer; complex political decisions concerning allocation and the crucial

The benefits of combining early aspecific vaccination with later specific vaccination

Timing is of crucial importance for successful vaccination. To avoid a large outbreak, vaccines are administered preferably as quickly as possible. However

Exploring insect cells versatility for production of influenza virus-like particles

A potential strategy to produce safer and broadly protective influenza vaccines is to co-express, in the same cell host, multiple hemagglutinins (HA) with a matrix protein (M1) which self-assemble in virus-like particles (VLPs). This study demonstrates the suitability of combining stable expression and the baculovirus-expression vector system (BEVs) in insect Hi5 cells for production of such multi-HA Influenza VLPs. Stable pools of Hi5 cells expressing two HAs were generated and later infected with a M1-encoding baculovirus at two cell concentrations (CCIs; 2×106 cells/mL and 3×106 cells/mL). The HA concentration in culture supernatant was followed over time, with more productive infections observed at higher CCIs. To extend the culture time, a re-feed strategy was implemented based on the identification of key nutrients which were exhausted during cell growth. Afterwards, supplemented cultures infected at a CCI of 4×106 cells/mL allowed a 4-fold increase in HA concentration, at harvest, when compared to cultures infected at a CCI of 2×106 cells/mL. The production of multi-HA influenza VLPs using the aforementioned strategy could be successfully scaled-up to 2L bioreactor cultures with even higher volumetric (1.5-fold) HA yields. To surpass the unpredictability of gene expression promoted by the random integration strategy mentioned above, the recombinase-mediated cassette exchange (RMCE) technology was explored. The feasibility of having two cassettes flanked by distinct pairs of flippase recognition target sites (FRTs) was evaluated. Unfortunately, significant cross-interaction was observed between the selected pairs. To circumvent this bottleneck, a backup strategy consisting in the co-expression of two genes from the same locus after implementation of one cassette system, in insect Sf9 cells, was attempted. However, the isolated clones showed low expression of both M1 and HA proteins. Ongoing work focuses on the isolation of clones tagged in high expression loci by fluorescence activated cell sorter technology. This work demonstrates how the versatility of insect cell expression technology can be explored to produce Influenza VLPs as vaccine candidates.A co-expressão de várias hemaglutininas (HA) e proteína da matriz (M1), no mesmo hospedeiro, formando partículas semelhantes a vírus (VLPs), constitui uma importante estratégia para desenvolver vacinas contra o vírus da gripe. Este trabalho mostra a combinação de uma linha celular estável de células de insecto com o sistema de expressão mediada por baculovírus para a produção deste tipo de VLPs. Foram estabelecidas duas populações de células de insecto Hi5, expressando duas HAs, posteriormente infectadas com um baculovírus contendo a proteína M1, a duas concentrações celulares diferentes (CCI; 2 e 3×106 cells/mL) sendo que a mais elevada demostrou ser a mais produtiva. De seguida, implementou-se uma estratégia baseada na adição de nutrientes específicos para prolongar o tempo de cultura. As culturas previamente suplementadas e infectadas a uma CCI de 4×106 células/mL produziram 4x mais HA comparativamente às culturas infectadas a uma CCI de 2×106 células/mL, não suplementadas. Esta estratégia foi também aplicada num biorreactor de 2L permitindo 1,5x mais produção, volumétrica, de HA comparativamente a experiências em pequena escala. De forma a ultrapassar a imprevisibilidade de uma integração aleatória, foi explorado o sistema de troca de cassete mediado por recombinase (RMCE). A viabilidade de um sistema com duas cassetes integradas flanqueadas por diferentes locais de reconhecimento (FRTs) foi avaliada, tendo sido observada a interação entre ambos os pares selecionados. Como segunda estratégia, foi implementado um sistema com uma cassete para co-expressão de dois genes em simultâneo, em células de insecto Sf9. Porém, os clones isolados mostram fraca expressão de M1 e HA, pelo que uma estratégia de isolamento de clones com expressão génica mais forte está em desenvolvimento utilizando uma tecnologia de sorteamento. Assim, este trabalho demonstra a versatilidade da tecnologia aplicada em células de insecto, que pode ser explorada para produzir VLPs multivalentes, com potencial para se tornar a próxima geração de vacinas para o vírus da gripe

Operational issues and network effects in vaccine markets

One of the most important concerns for managing public health is the prevention of infectious diseases. Although vaccines provide the most effective means for preventing infectious diseases, there are two main reasons why it is often difficult to reach a socially optimal level of vaccine coverage: (i) the emergence of operational issues (such as yield uncertainty) on the supply side, and (ii) the existence of negative network effects on the consumption side. In particular, uncertainties about production yield and vaccine imperfections often make manufacturing some vaccines a risky process and may lead the manufacturer to produce below the socially optimal level. At the same time, negative network effects provide incentives to potential consumers to free ride off the immunity of the vaccinated population. In this research, we consider how a central policy-maker can induce a socially optimal vaccine coverage through the use of incentives to both consumers and the vaccine manufacturer. We consider a monopoly market for an imperfect vaccine; we show that a fixed two-part subsidy is unable to coordinate the market, but derive a two-part menu of subsidies that leads to a socially efficient level of coverage

Stockpiling and resource allocation for influenza preparedness and manufacturing assembly

textStockpiling resources is a pervasive way to handle demand uncertainty and future demand surges. However, stockpiling is subject to costs, including warehousing costs, inventory holding costs, and wastage of expired resources. Hence, how to stockpile in an economically efficient manner is an important topic to study. Furthermore, if the inventoried supply is insufficient for a surge in demand, how to best allocate available resources becomes a natural question to ask. In this dissertation, we consider three applications of stockpiling and resource allocation: (i) we stockpile ventilators both centrally and regionally for an influenza pandemic; (ii) we allocate limited vaccine doses of various types to target populations for an influenza pandemic; and, (iii) we investigate inventory needs for low cost, high usage (class C) parts in an engine assembly plant. First, we describe and analyze a model for estimating the number of ventilators that the Texas Department of State Health Services (DSHS), and eight health service regions in Texas, should stockpile for an influenza pandemic. Using a probability distribution governing peak-week demand for ventilators across the eight health service regions, an optimization model allows investigation of the tradeoff between the cost of the total stockpile and the expected shortfall of ventilators under mild, moderate, and severe pandemic scenarios. Our analysis yields the surprising result that there is little benefit to DSHS holding a significant stockpile, even when those centrally held ventilators can be dispatched to regions after observing the peak-week demand realization. Three factors contribute to this result: positively correlated regional demands, a relatively low coefficient of variation, and wastage of the central stockpile once it is dispatched to the regions. Second, we formulate an optimization model for allocating various types of vaccines to multiple priority groups in 254 counties in the state of Texas that DSHS can use to distribute its vaccines for an influenza pandemic. For reaching the public, vaccines are allocated to the state’s Registered Providers (RPs), Local Health Departments (LHDs), and Health Service Regions (HSRs). The first two allocations are driven by requests from RPs and LHDs while HSR allocation is at DSHS’s discretion. The optimization model aims to achieve proportionally fair coverage of priority groups across the 254 counties, as informed by user-specified weights on those priority groups, using the HSR doses. With proportional fairness as our primary goal, the optimal allocation also counts policy simplicity and regional equity. Sensitivity analysis on the portion of the state’s vaccines reserved for HSRs shows that a small portion can effectively shrink the gap of vaccination coverage between urban and rural counties. Finally, we derive short-cut formulae for estimating the extra inventory needed for managing class C parts in units of bins that an engine assembly plant can use to achieve a desired fill rate at workstations. The plant orders a class C part from its supplier based on the part’s aggregated next-day demand across all workstations. After receiving the part, the plant first stores the supply in the warehouse and delivers the part to workstations in bins whenever the line-side inventory at a workstation is empty. We study four cases of various information availability in the order quantity calculation and derive associated formulae for estimating the extra inventory needed due to demand aggregation and bin delivery. We demonstrate the performance of our short-cut formulae, showing the tradeoff between extra inventory needed and the associated risk of not satisfying all workstation requests. Our sensitivity analysis shows that workstation demand variation and bin size have little or no influence on the performance of our short-cut formulae.Operations Research and Industrial Engineerin

A review of the healthcare-management (modeling) literature published at Manufacturing and Service Operations Management

Healthcare systems throughout the world are under pressure to widen access, improve efficiency and quality of care, and reduce inequity. Achieving these conflicting goals requires innovative approaches, utilizing new technologies, data analytics, and process improvements. The operations management community has taken on this challenge: more than 10% of articles published in M&SOM in the period from 2009 to 2018 has developed analytical models that aim to inform healthcare operational decisions and improve medical decision-making. This article presents a review of the research published in M&SOM on healthcare management since its inception 20 years ago and reflects on opportunities for further research

Improving downstream processing for viral vectors and viral vaccines

Viral vectors are playing an increasingly important role in the vaccine and gene therapy elds. The broad spectrum of potential applications, together with expanding medical markets, drives the e orts to improve the production processes for viral vaccines and viral vectors. Developing countries, in particular, are becoming the main vaccine market. It is thus critical to decrease the cost per dose, which is only achievable by improving the production process. In particular advances in the upstream processing have substantially increased bioreactor yields, shifting the bioprocess bottlenecks towards the downstream processing. The work presented in this thesis aimed to develop new processes for adenoviruses puri cation. The use of state-of-the-art technology combined with innovative continuous processes contributed to build robust and cost-e ective strategies for puri cation of complex biopharmaceuticals.(...