Funding vaccines for emerging infectious diseases

ABSTRACT

Immunization has played a large role in substantially reducing the infected and death tolls from infectious diseases. In the case of emerging diseases, the identity of the pathogen responsible, as well as the time and location for the next outbreak, cannot be accurately predicted using current means. Coupled with disjointed efforts towards the development of vaccines and a lack of funds and desire to advance promising products against known emerging pathogens to clinical trials, there has been a shortage of approved products ready for emergency use. Recent outbreaks have exposed these weaknesses, and the Coalition for Epidemic Preparedness Innovations (CEPI) was created in 2016 to address these issues. In this commentary, we discuss the establishment of such a global vaccine fund, and provide some additional points to consider for stimulating further discussion on this comprehensive, ambitious initiative.

KEYWORDS:

• Ebola
• influenza
• funding
• MERS
• SARS
• vaccine
• vaccinology
• Zika

Emerging infectious diseases are considered as such if they appear for the first time in a population or if they are rapidly increasing in geographic range or the incidence of cases (i.e. an outbreak). Unlike other pathogens, emerging infectious diseases pose a unique threat in that health authorities will often have little to no prior experience with the prevention and control of these pathogens. From the beginning of the 21^st century to the present, the world has experienced several high-profile outbreaks of emerging infectious disease caused by novel or obscure, neglected pathogens: SARS-CoV in 2003–04 originating in China, H1N1 “swine flu” in 2009 from Mexico, MERS-CoV since 2012 originating in Saudi Arabia, Ebola virus (EBOV) from 2013–16 originating in Guinea, and Zika virus (ZIKV) during 2015–16 originating in Brazil. In each instance, it was not possible to predict the time, location or identity of the causative pathogen beforehand. Indeed, prior to the EBOV and ZIKV outbreaks in 2013 and 2015, respectively, both were considered neglected tropical pathogens. Both SARS-CoV and MERS-CoV were novel pathogens reported for the first time, and emerging influenza viruses were typically novel pathogens derived from genetic evolution and reassortment. Other factors such as urbanization have led to increased contact between human populations and wild animals potentially carrying novel zoonotic diseases. Furthermore, factors such as globalization have resulted in the increased movement of people (and thus pathogens) across national borders, and climate change may facilitate the spread and transmission of certain pathogens as well as changes in the geographical distribution of reservoir hosts and/or vectors.

Vaccination is currently the best defence we have against these unpredictable outbreaks of emerging disease, and the complete process for bringing a vaccine from the research laboratory to the population in need can be described in four stages.¹ Stage 1 consists of the discovery phase, in which vaccine candidates are developed and characterized in animal models; Stage 2 is the development and licensure phase, in which the product at hand is advanced through clinical trials; Stage 3 is the manufacturing phase, in which there is GMP-level production of the vaccine on a large scale; and Stage 4 is the delivery and stockpiling phase, in which the manufactured product is delivered to populations residing at the most at-risk locations, as well as accumulated and stored in various locations in preparation for use during an outbreak.

With the development of a new vaccine requiring a capital investment of $500 million to $1 billion dollars² and typically a 10 year minimum to advance the vaccine from bench to bedside, there is a lack of incentive from agencies to fund research into and develop vaccines against obscure pathogens that may or may not cause outbreaks in humans; especially with so many other pathogens that already affect millions still lacking a vaccine or having sub-optimal vaccines such as the HIV or hepatitis B viruses, and the influenza virus, respectively. As noted previously, fragmented vaccine-development efforts, and uncoordinated government funding (i.e. without a clear plan that addresses global threats internationally) have resulted in too many missed opportunities to efficiently bring an efficacious vaccine to market before an epidemic strikes.³ A recent example is the 2013–16 EBOV outbreak in West Africa, in which two promising candidates, namely the adenovirus-vectored (Ad5-GP)⁴ and the vesicular stomatitis virus-vectored (VSVΔG/EBOVGP) ⁵ vaccines had been tested in nonhuman primates in 2003 and 2005, respectively. However, only Ad5-GP was subsequently evaluated in Phase I clinical trials⁶ during 2010 and was not investigated further, despite positive immunogenicity and safety data.

It was clear that improvements needed to be made to the current system of vaccine development, and several world-renowned experts have proposed the establishment of a global vaccine-development fund to “provide the resources and momentum to carry vaccines from their conception in academic and government laboratories and small biotechnology firms to development and licensure by the industry”.⁷ In response, the Bill and Melinda Gates Foundation, the World Economic Forum, Wellcome Trust and the governments of Norway and India co-founded the Coalition for Epidemic Preparedness Innovations (CEPI) in 2016, which aims to “stimulate, finance and coordinate the development of vaccines against epidemic diseases, especially in cases in which market incentives alone are insufficient”.³ Other entities, such as the governments of Germany and Japan, have since joined as investors. As a funder, CEPI plans to bridge the gaps in development and provision by funding promising vaccines with a five-year goal of accelerating four potential candidates against 2–3 high priority pathogens to the stage where safety and efficacy will be demonstrated, such that the vaccines will be ready for Phase III testing (or potentially deployment) in the event of an outbreak. As a facilitator, CEPI plans to collaborate with the industry, regulators and other relevant organizations to improve regulatory preparedness, as well as ensure that vaccines with proven safety and efficacy are licensed and reach the populations who need them the most.⁸ CEPI will initially focus on a list of blueprint priority diseases that the World Health Organization (WHO) has revealed in January 2017,⁹ which currently consists of Lassa Fever, Crimean Congo Hemorrhagic Fever, Ebola and Marburg virus disease, MERS, SARS, Nipah and other henipavirus diseases, Rift Valley Fever, Severe Fever with Thrombocytopenia Syndrome and Zika Fever. The causative pathogens behind these diseases are all known threats to public health.

There are some points to consider when implementing such an ambitious, end-to-end vaccine initiative. First, funding for vaccine research should not be isolated from other areas of outbreak control, such as surveillance efforts. Recent studies have indicated that highly pathogenic H5N8 has spread from Asia into Europe and North America,¹⁰ and in China, a “hotbed” for the emergence of novel influenza viruses, findings indicate that H5N6 has become the dominant circulating subtype in southern China since at least 2015, causing several human deaths.¹¹ Other outbreak viruses may also be prone to mutations and as such stockpiled vaccines may need to be updated speedily and effectively in case of anticipated failure. Second, the exact geographical locations in which known viruses circulate may not always be accurate. For instance, EBOV, thought to be mainly in Central Africa, unexpectedly emerged in Western Africa in 2013. Therefore, not only is stockpiling important, but logistics need to be resolved such a way that existing vaccine stocks can be moved at short notice to contain the number of cases in outbreak areas. Third, each emerging pathogen poses its unique differences and challenges, and the current stage of vaccine development varies widely between each disease. For instance, with EBOV the main bottleneck was the lack of support to advance promising products through the clinical pipeline, but there are not as many choices for experimental vaccines against other related viruses, such as BDBV and TAFV, due in part to the lack of a small animal model to screen antivirals in an efficient manner. Similarly, the main bottleneck for SARS-CoV and MERS-CoV vaccine development is the lack of a widely available, susceptible/lethal small animal model. Therefore, funding efforts may need to focus on different stages of development depending on the pathogen in question. Fourth, vaccine delivery should also be accompanied by outreach efforts, such as education of the local populace on general information regarding infectious diseases and existing countermeasures, in order to promote wider acceptance for immunization during non-outbreak times. Finally, there is always the possibility of a completely novel, previously undiscovered pathogen that emerges to wreak havoc. Rather than disrupting ongoing vaccine research efforts by redirecting existing funds or attempting to fund-raise during an emergency, it may be better to set aside “rainy day” funds that can be unlocked for immediate use in this scenario.

The coordination of efforts to provide much-needed funding to develop, accelerate and advance promising vaccine candidates represents a strategic investment that will save untold numbers of lives and reduce excessive spending in the future. If those in charge of implementing the plan are flexible, receptive, and adaptable to ever-changing circumstances, with solid contingency plans in place, this initiative will undoubtedly be a positive contribution to the global war on infectious diseases.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This work is supported by the National Key Research and Development Program of China (2016YFE0205800), the National Key Program for Infectious Disease of China (2016ZX10004222), the Public Health Agency of Canada, partially supported by grants from the National Institutes of Health (U19AI109762-1) and Canadian Institutes of Health Research (IER–143487), the Sanming Project of Medicine in Shenzhen (ZDSYS201504301534057), the Shenzhen Science and Technology Research and Development Project (JCYJ20160427151920801), and the National Natural Science Foundation of China International Cooperation and Exchange Program (816110193). The authors declare no competing financial interests.