The cost and challenge of vaccine development for emerging and emergent infectious diseases

Over the past two decades, new infectious threats have emerged almost yearly.1Bloom DE Black S Rappuoli R Emerging infectious diseases: a proactive approach.Proc Natl Acad Sci USA. 2017; 114: 4055-4059Crossref PubMed Scopus (113) Google Scholar Outbreaks of Ebola virus disease, severe acute respiratory syndrome, Middle East respiratory syndrome, and Zika virus disease were interspersed between epidemics of H5N1 and H7N9 avian, swine, and H1N1 influenza. While most developed countries focused on these, disease due to Lassa, Nipah, and Crimean-Congo haemorrhagic fever viruses continued unabated. Other emergent pathogens such as severe fever and thrombocytopenia syndrome virus, and Powassan virus remain restricted in scope. When, in 2014, Ebola was detected in the capital cities of Guinea, Liberia, and Sierra Leone, the potential for a global pandemic expanding from travellers from affected regions or repatriation of infected health-care workers became a real concern. Ebola recalled the 2002 severe acute respiratory syndrome outbreaks in Hong Kong and Toronto and raised alarm during the 2015 Middle East respiratory syndrome outbreak in South Korea. And Zika, previously considered as self-limited, was newly associated with Guillain–Barré syndrome and fetal abnormalities.2European Centre for Disease Prevention and ControlRapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain–Barré syndrome—10 December 2015.https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdfDate: 2015Date accessed: January 30, 2016Google Scholar The Ebola, severe acute respiratory syndrome, Middle East respiratory syndrome, and Zika outbreaks each highlighted substantial and varied gaps in vaccine development.3Maslow JN Vaccine development for emerging infectious diseases.Vaccine. 2017; 35: 5437-5443Crossref PubMed Scopus (23) Google Scholar First, vaccine research was reactive. Even for Ebola, despite three decades of vaccine research, human trials were limited to two vaccine candidates in the early to mid-2000s.4Ledgerwood JE Costner P Desai N et al.A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults.Vaccine. 2011; 29: 304-313Crossref Scopus (183) Google Scholar, 5Martin JE Sullivan NJ Enama ME et al.A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial.Clin Vaccine Immunol. 2006; 13: 1267-1277Crossref PubMed Scopus (216) Google Scholar Second, vaccine trials occurred during epidemics with an evolving epidemiology. And third, while funding materialised to combat each outbreak, interest and financial support waned as case prevalences fell and imminent danger receded. These issues highlighted the urgent need for a coordinated and consistent approach to vaccine development for emerging and emergent pathogens. In this context, WHO identified the need for coordination of countermeasures6Kieny MP Rottingen JA Farrar J WHO R&D Blueprint team, R&D Blueprint Scientific Advisory GroupThe need for global R&D coordination for infectious diseases with epidemic potential.Lancet. 2016; 388: 460-461Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar and convened a consultation to develop a so-called blueprint for infectious diseases with epidemic potential.7WHOAnnual review of diseases prioritized under the Research and Development Blueprint. Information consultation, 24–25 January 2017.http://www.who.int/blueprint/what/research-development/2017-Prioritization-Long-Report.pdf?ua=1Date: 2017Date accessed: June 1, 2017Google Scholar Although organisations such as the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Biomedical Advanced Research and Development Authority have provided substantial support for select projects and focus areas, their missions are broader than vaccine research. The Coalition of Epidemic Preparedness Innovations (CEPI) was conceived to address this shortcoming. In this issue of The Lancet Global Health, Dimitrios Gouglas and colleagues8Gouglas D Thanh Le T Henderson K et al.Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study.Lancet Glob Health. 2018; (published online Oct 17.)http://dx.doi.org/10.1016/S2214-109X(18)30346-2Summary Full Text Full Text PDF PubMed Scopus (139) Google Scholar present a cost analysis for vaccine development for epidemic infectious diseases. Such an analysis is crucial to serve as a guide to harmonise finite funds and monetary needs to achieve CEPI's goal of successful testing through phase 2a of at least one vaccine per targeted pathogen. Although not part of CEPI's mandate, the eventual objective is successful vaccine licensure. For the 11 priority pathogens identified in the WHO blueprint,7WHOAnnual review of diseases prioritized under the Research and Development Blueprint. Information consultation, 24–25 January 2017.http://www.who.int/blueprint/what/research-development/2017-Prioritization-Long-Report.pdf?ua=1Date: 2017Date accessed: June 1, 2017Google Scholar 224 candidate vaccines in preclinical and clinical development were identified. The probability of success for a vaccine to advance to successive stages was modelled from the literature, with a 40–50% chance of advancement from preclinical to clinical studies and a composite prevalence of success through phase 2 of 10–13%. Gouglas and colleagues' actual data show that only 10·7% of vaccines have advanced to phase 1 and 2·7% to phase 2. Although consistent, these figures are slightly lower than the 10% prevalence of drug candidate licensure estimated by DiMasi and colleagues.9DiMasi JA Grabowski HG Hansen RW Innovation in the pharmaceutical industry: new estimates of R&D costs.J Health Econ. 2016; 47: 20-33Crossref PubMed Scopus (1897) Google Scholar Gouglas and colleagues' stochastic model was based on actual expenditures provided by vaccine developers for pipeline vaccines. As the authors note, the accuracy of self-reported cost figures are unknown; also the prevalence of reporting was not provided. For some disease programmes, cost data might be rudimentary because work is ongoing. The cost of development through phase 2a, not including the initial discovery, was calculated as US$31–68. Including the risk of candidate non-advancement, costs per successful candidate could range from $319 to 469 million, consistent with cost estimates through licensure of $2·5 billion per successful candidate.8Gouglas D Thanh Le T Henderson K et al.Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study.Lancet Glob Health. 2018; (published online Oct 17.)http://dx.doi.org/10.1016/S2214-109X(18)30346-2Summary Full Text Full Text PDF PubMed Scopus (139) Google Scholar Using these cost estimates, the total portfolio cost to advance at least one candidate vaccine through to phase 2a for each of the 11 target pathogens was $3·5–5·2 billion; a point at which stockpiling could conceivably occur. One can ask whether there is a way to reduce both time and cost through phase 2 and eventual licensure while increasing potential for success. CEPI's funding model of parallel development of multiple candidates and a focus on platforms with previous known success are key to limiting time and cost. Another area not considered here is the ability to do efficacy trials, which might not be feasible for uncommon or geographically dispersed diseases such as severe fever with thrombocytopenia syndrome virus, Powassan virus, severe acute respiratory syndrome, and Middle East respiratory syndrome, although a potential solution might be to consider group-specific approvals on the basis of success of a vaccine platform for related viruses. Finally, the CEPI model provides the impetus for early-phase vaccine development for diseases with unknown commercial return; solutions to encourage development through licensure are, however, still needed. I am Chief Medical Officer and a paid employee of GeneOne Life Science. GeneOne is developing DNA vaccines for MERS-CoV, Zika virus, and the SFTS virus. Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation studyOur analysis provides new evidence on vaccine research and development pipelines and associated costs for 11 epidemic infectious diseases, highlighting both funding needs and research and development gaps for achieving vaccine research and development preparedness targets. Full-Text PDF Open Access

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