A strategic model for developing vaccines against neglected diseases: An example of industry collaboration for sustainable development.

Infectious diseases continue to disproportionately affect low- and middle-income countries (LMICs) and children aged <5 y. Developing vaccines against diseases endemic in LMICs relies mainly on strong public-private collaborations, but several challenges remain. We review the operating model of the GSK Vaccines Institute for Global Health (GVGH), which aims to address these challenges. The model involves i) selection of vaccine targets based on priority ranking for impact on global health; ii) development from design to clinical proof-of-concept; iii) transfer to an industrial partner, for further technical/clinical development, licensing, manufacturing, and distribution. Cost and risks associated with pre-clinical and early clinical development are assumed by GVGH, increasing the probability to make the vaccine more affordable in LMICs. A conjugate vaccine against typhoid fever, Vi-CRM197, has recently obtained WHO prequalification, within a year from licensure in India, demonstrating the success of the GVGH model for development and delivery of global health vaccines.

A re-assessment of 4CMenB vaccine effectiveness against serogroup B invasive meningococcal disease in England based on an incidence model.

BACKGROUND: The four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model. METHODS: Aggregate data-stratified by age, year and doses received-were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011-2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received. RESULTS: The incidence model showed that cases decreased until 2013-2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%]95%BCI and after two doses, 78.7% [71.5%; 84.5%]95%BCI. We estimated that vaccination averted 312 cases [252; 368]95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction. CONCLUSIONS: Our estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

Vaccines: An achievement of civilization, a human right, our health insurance for the future.

Vaccines have made a key, cost-effective contribution to the prolongation of life expectancy and quality. Here we summarize challenges facing vaccinology and immunology at the level of society, scientific innovation, and technology in a global health perspective. We argue that vaccines represent a safety belt and life insurance for humankind.

Sustainable vaccine development: a vaccine manufacturer's perspective.

Vaccination remains the most cost-effective public health intervention after clean water, and the benefits impressively outweigh the costs. The efforts needed to fulfill the steadily growing demands for next-generation and novel vaccines designed for emerging pathogens and new indications are only realizable in a sustainable business model. Vaccine development can be fast-tracked through strengthening international collaborations, and the continuous innovation of technologies to accelerate their design, development, and manufacturing. However, these processes should be supported by a balanced project portfolio, and by managing sustainable vaccine procurement strategies for different types of markets. Collectively this will allow a gradual shift to a more streamlined and profitable vaccine production, which can significantly contribute to the worldwide effort to shape global health.

Improving accountability in vaccine decision-making.

INTRODUCTION: Healthcare decisions, in particular those affecting entire populations, should be evidence-based and taken by decision-makers sharing broad alignment with affected stakeholders. However, criteria, priorities and procedures for decision-making are sometimes non-transparent, frequently vary considerably across equivalent decision-bodies, do not always consider the broader benefits of new health-measures, and therefore do not necessarily adequately represent the relevant stakeholder-spectrum. Areas covered: To address these issues in the context of the evaluation of new vaccines, we have proposed a first baseline set of core evaluation criteria, primarily selected by members of the vaccine research community, and suggested their implementation in vaccine evaluation procedures. In this communication, we review the consequences and utility of stakeholder-centered core considerations to increase transparency in and accountability of decision-making procedures, in general, and of the benefits gained by their inclusion in Multi-Criteria-Decision-Analysis tools, exemplified by SMART Vaccines, specifically. Expert commentary: To increase effectiveness and comparability of health decision outcomes, decision procedures should be properly standardized across equivalent (national) decision bodies. To this end, including stakeholder-centered criteria in decision procedures would significantly increase their transparency and accountability, support international capacity building to improve health, and reduce societal costs and inequity resulting from suboptimal health decision-making.

Towards a more comprehensive approach for a total economic assessment of vaccines?: 1. The building blocks for a health economic assessment of vaccination.

​Since we were born, we all take preventative actions to avoid unpredictable adverse conditions. Some actions are done automatically. Others require a conscious choice , either for personal or social benefit. A distinction can therefore be drawn between non-active and active prevention, and between individual and social prevention. Active prevention requires making a choice in time, effort, and cost. We call it an economic choice. Vaccines belong to the group of active and social prevention. Because a vaccination program is an economic social choice, how should it be valued, and what cost should we pay for? To date, the economic evaluations developed for treatment have been applied to vaccines. However, over 25 different characteristics differentiate vaccines from treatment. For example, the benefit of vaccination is measured at the population level not at the individual level, the main effect of prevention is societal and not an individual-based gain only, and the biggest hurdle to implement a new vaccine is the initial budget investment and not so much its estimated 'value for money'. This makes the current application of incremental cost-utility analysis difficult for vaccines for a comprehensive evaluation. New approaches may be needed to capture the full economic benefit of vaccines.​.

2. How is the economic assessment of vaccines performed today?

This paper describes how the economic assessment of vaccines is performed today. It discusses why it may be incomplete and explores potential approaches to adjust the analysis to be more comprehensive. Besides helping protect against serious disease, vaccines also help avoid mild disease episodes that may not receive medical attention but which have important societal consequences. They also benefit unvaccinated individuals by reducing disease transmission. Wider societal benefits may extend beyond a decrease in disease incidence, as lower transmission rates reduce the risk of epidemics, which in turn reduces the pressure on healthcare providers, and may improve the quality of care for patients with unrelated diseases. Vaccines also lower the use of antibiotics leading to less pressure on anti-microbial resistance. Conventional ICUA focuses on individual health benefits, like increased survival. Therefore, this approach may not adequately capture the wider vaccination benefits. We discuss differences between treatment and vaccine prevention in the economic assessment, and how ICUA has been adapted to cope with the inconsistencies. Although such adaptations may fulfil the demand of one specific stakeholder, they may not meet the needs of other stakeholders who operate at the societal level, such as ministries other than healthcare, employers, caregivers, and insurers.

3. How comprehensive can we be in the economic assessment of vaccines?

In two previous papers we argued on current vaccines economic assessment not fully comprehensive when using the incremental cost-utility analysis normally applied for treatments. Many differences exist between vaccines and drug treatments making vaccines economic evaluation more cumbersome. Four challenges overwhelmingly present in vaccines assessment are less important for treatments: requirements for population, societal perspectives, budget impact evaluation, and time focused objectives (control or elimination). Based on this, economic analysis of vaccines may need to be presented to many different stakeholders with various evaluation preferences, in addition to the current stakeholders involved for drugs treatment assessment. Then, we may need a tool making the inventory of the different vaccines health economic assessment programmes more comprehensive. The cauliflower value toolbox has been developed with that aim, and its use is illustrated here with rotavirus vaccine. Given the broader perspectives for vaccine assessment, it provides better value and cost evaluations. Cost-benefit analysis may be the preferred economic assessment method when considering substitution from treatment to active medical prevention. Other economic evaluation methods can be selected (i.e. optimisation modelling, return on investment) when project prioritisation is the main focus considered and when stakeholders would like to influence the development of the healthcare programme.

Beyond cost-effectiveness: Using systems analysis for infectious disease preparedness.

Until the recent outbreaks, Ebola vaccines ranked low in decision makers' priority lists based on cost-effectiveness analysis and (or) corporate profitability. Despite a relatively small number of Ebola-related cases and deaths (compared to other causes), Ebola vaccines suddenly leapt to highest priority among international health agencies and vaccine developers. Clearly, earlier cost-effectiveness analyses badly missed some factors affecting real world decisions. Multi-criteria systems analysis can improve evaluation and prioritization of vaccine development and also of many other health policy and investment decisions. Neither cost-effectiveness nor cost-benefit analysis can capture important aspects of problems such as Ebola or the emerging threat of Zika, especially issues of inequality and disparity-issues that dominate the planning of many global health and economic organizations. Cost-benefit analysis requires assumptions about the specific value of life-an idea objectionable to many analysts and policy makers. Additionally, standard cost-effectiveness calculations cannot generally capture effects on people uninfected with Ebola for example, but nevertheless affected through such factors as contagion, herd immunity, and fear of dread disease, reduction of travel and commerce, and even the hope of disease eradication. Using SMART Vaccines, we demonstrate how systems analysis can visibly include important "other factors" and more usefully guide decision making and beneficially alter priority setting processes.

Core values for vaccine evaluation.

Currently, most health economic modelling approaches tend to inadequately incorporate crucial disease-specific criteria and other attributes of benefit resulting from vaccination, which limits their utility for evaluating vaccines and, in consequence, for optimally guiding vaccine decision-making. Additionally, vaccine evaluation methods are frequently poorly standardised and non-transparent, leading to a potentially low level of accountability that can hinder acceptance of resulting decisions. To address these issues, we have considered whether it is possible to identify a set of universal vaccine-disease considerations, which we have called Core Values. To begin to identify such a set of criteria, and to establish whether strong agreement around such core values exists, we conducted two studies based on the Delphi technique. Both studies surveyed a cohort consisting of expert members of the global vaccine community with diverse professional backgrounds. Formal statistical analysis of both studies identified four attributes with strong agreement: 1. Incidence disease cases prevented per year, 2. Cost-effectiveness (including cost-benefit and cost-utility analysis), 3. High mortality disease (case-fatality-rate), and 4. Severity of target disease (risk of morbidity and mortality). These results suggest the feasibility of identifying a clear consensus on a specific set of Core Values for Vaccine Evaluation.

Multicriteria decision analysis and core values for enhancing vaccine-related decision-making.

Vaccines have the potential to transform the health of all individuals and to reduce the health inequality between rich and poor countries. However, to achieve these goals, it is no longer sufficient to prioritize vaccine development using cost-effectiveness as the sole indicator. During a symposium entitled "Mission Grand Convergence-The Role of Vaccines," held in Siena, Italy, in July 2015, key stakeholders agreed that the prioritization of vaccine development and deployment must use multicriteria decision-making based on the following core concepts: (i) mortality and severity of the disease, (ii) vaccine safety considerations, and (iii) economic evaluation that captures the full benefits of vaccination.

Strategic Planning in Population Health and Public Health Practice: A Call to Action for Higher Education.

POLICY POINTS: Scarce resources, especially in population health and public health practice, underlie the importance of strategic planning. Public health agencies' current planning and priority setting efforts are often narrow, at times opaque, and focused on single metrics such as cost-effectiveness. As demonstrated by SMART Vaccines, a decision support software system developed by the Institute of Medicine and the National Academy of Engineering, new approaches to strategic planning allow the formal incorporation of multiple stakeholder views and multicriteria decision making that surpass even those sophisticated cost-effectiveness analyses widely recommended and used for public health planning. Institutions of higher education can and should respond by building on modern strategic planning tools as they teach their students how to improve population health and public health practice. CONTEXT: Strategic planning in population health and public health practice often uses single indicators of success or, when using multiple indicators, provides no mechanism for coherently combining the assessments. Cost-effectiveness analysis, the most complex strategic planning tool commonly applied in public health, uses only a single metric to evaluate programmatic choices, even though other factors often influence actual decisions. METHODS: Our work employed a multicriteria systems analysis approach--specifically, multiattribute utility theory--to assist in strategic planning and priority setting in a particular area of health care (vaccines), thereby moving beyond the traditional cost-effectiveness analysis approach. FINDINGS: (1) Multicriteria systems analysis provides more flexibility, transparency, and clarity in decision support for public health issues compared with cost-effectiveness analysis. (2) More sophisticated systems-level analyses will become increasingly important to public health as disease burdens increase and the resources to deal with them become scarcer. CONCLUSIONS: The teaching of strategic planning in public health must be expanded in order to fill a void in the profession's planning capabilities. Public health training should actively incorporate model building, promote the interactive use of software tools, and explore planning approaches that transcend restrictive assumptions of cost-effectiveness analysis. The Strategic Multi-Attribute Ranking Tool for Vaccines (SMART Vaccines), which was recently developed by the Institute of Medicine and the National Academy of Engineering to help prioritize new vaccine development, is a working example of systems analysis as a basis for decision support.

Delivering vaccines to the people who need them most.

Thanks to the Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation, the global health community has made enormous progress in providing already existing vaccines to developing countries. However, there still exists a gap to develop vaccines for which there is no market in the Western world, owing to low economic incentives for the private sector to justify the investments necessary for vaccine development. In many cases, industry has the technologies, but lacks the impetus to direct resources to develop these vaccine products. The present emergency with the Ebola vaccine provides us an excellent example where a vaccine was feasible several years ago, but the global health community waited for a humanitarian disaster to direct efforts and resources to develop this vaccine. In the beginning of 2015, the first large-scale trials of two experimental vaccines against Ebola virus disease have begun in West Africa. During the past few years, several institutions have dedicated efforts to the development of vaccines against diseases present only in low-income countries. These include the International Vaccine Institute, the Novartis Vaccines Institute for Global Health, the Hilleman Institute, the Sabin Vaccine Institute and the Infectious Disease Research Institute. Nevertheless, solving this problem requires a more significant global effort than that currently invested. These efforts include a clear policy, global coordination of funds dedicated to the development of neglected disease and an agreement on regulatory strategies and incentives for the private sector.

Developing vaccines for an aging population.

The demographics of the world's population are changing, with many adults now surviving into their 80s. With this change comes the need to protect the aging and other underserved populations not only against infectious diseases but also against cancer and other chronic conditions. New technologies derived from recent advances in the fields of immunology, structural biology, synthetic biology, and genomics have brought a revolution in the vaccine field. Among them, vaccine adjuvants have the potential to harness the immune system to provide protection against new types of diseases, improve protection in young children, and expand this protection to adults and the elderly. However, in order to do so we need also to overcome the nontechnical challenges that could limit the implementation of innovative vaccines, including controversies regarding the safety of adjuvants, increasing regulatory complexity, the inadequate methods used to assess the value of novel vaccines, and the resulting industry alienation from future investment. This Perspective summarizes the outcome of a recent multidisciplinary symposium entitled "Enhancing Vaccine Immunity and Value," held in Siena, Italy, in July 2014, that addressed two related questions: how to improve vaccine efficacy by using breakthrough technologies and how to capture the full potential of novel vaccines.

Vaccines, new opportunities for a new society.

Vaccination is the most effective medical intervention ever introduced and, together with clean water and sanitation, it has eliminated a large part of the infectious diseases that once killed millions of people. A recent study concluded that since 1924 in the United States alone, vaccines have prevented 40 million cases of diphtheria, 35 million cases of measles, and a total of 103 million cases of childhood diseases. A report from the World Health Organization states that today vaccines prevent 2.5 million deaths per year: Every minute five lives are saved by vaccines worldwide. Overall, vaccines have done and continue to do an excellent job in eliminating or reducing the impact of childhood diseases. Furthermore, thanks to new technologies, vaccines now have the potential to make an enormous contribution to the health of modern society by preventing and treating not only communicable diseases in all ages, but also noncommunicable diseases such as cancer and neurodegenerative disorders. The achievement of these results requires the development of novel technologies and health economic models able to capture not only the mere cost-benefit of vaccination, but also the value of health per se.