There are still major infectious diseases that required an effective vaccine for control and ultimate elimination, such as HIV infection and tuberculosis. Therefore, the continuing development of new vaccines is a public health imperative. Unfortunately, most early vaccine candidates in the discovery phase never make it as a safe and effective product. Development and deployment of vaccines is a long and complex process. We briefly describe here four hurdles that need to be overcome from the discovery phase of a new vaccine to sustainable population impact (Table 3).

Table 3 From discovery to sustainable effect of immunization: overcoming four major hurdles Full size table

The first hurdle is a ‘valley of death’ from discovery to early clinical development, when a potential antigen, adjuvant or new vaccine formulation developed in the laboratory is further tested for clinical proof-of-concept and safety in humans, in addition to optimizing production elements. Real progress has been made in recent years owing to several public and private initiatives that are helping partly to overcome this first major challenge, such as the Coalition for Epidemic Preparedness Innovation (CEPI)53, which was created after the 2014–2015 Ebola epidemic in West Africa to accelerate the development of vaccines against epidemic pathogens2,4,54.

The second hurdle in vaccine development, also referred to as the ‘second valley of death’, relates to the shift from early clinical development to the large and very expensive efficacy trials most often needed4, unless a previous similar vaccine is already developed and a new product can be licensed using an established correlate of immunity or protection. This is also the most expensive phase of vaccine development, absorbing more than two-thirds of the total costs of development of a new vaccine, including the building of special manufacturing facilities and conducting phase 3 trials in several countries, ideally with independent research partners. Often, this major financial effort is beyond the means of smaller biotech companies, and in general only big pharmaceutical companies and large foundations or public institutions have the financial bandwidth to support such trials that can cost as much as hundreds of millions of dollars. For vaccine candidates without a prospect of a high-income market to ensure a return on investment, and when the potential market for the new vaccine is limited to low- and middle-income countries, there is an almost unsurmountable valley of death unless philanthropic and public funding intervene2.

The needs and unique challenges of vaccines against epidemic pathogens demand innovation in product development pathways. The Merck recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV–ZEBOV) vaccine was deployed on a large scale during the recent Ebola outbreak in eastern Democratic Republic of the Congo before the product was licensed—even for indications for which no efficacy data were available such as primary prevention in healthcare workers. A second experimental vaccine, Ad26.ZEBOV/MVA-BN-Filo, is now also deployed for the same outbreak and in Rwanda55. Well-informed country leadership and transparent governance of such use are crucial, as is genuine community involvement. The ‘animal efficacy rule’ that applies when efficacy trials in humans are not feasible or ethical56 should also be considered for vaccines against epidemic pathogens. The development of Ebola vaccines has shown how this type of ‘learning by doing’ model can offer early access in humanitarian situations55,57, although it should be stressed that nearly five years after the first Ebola vaccine clinical trials in West Africa, no Ebola vaccine is licensed despite well-documented immunogenicity, safety, and human and/or non-human primate efficacy data. When a crisis such as Ebola is no longer the headline news, the sense of urgency is lost, and regulators and normative committees go back to often extraordinarily long processes.

After a successful phase 3 trial, there is a complex path to the licensing of any new vaccine, which requires reproducibility and safety tests of several batches of vaccines, while manufacturing facilities are finalized. Many countries still request clinical trial data conducted locally, delaying country licensing and implementation considerably, while further raising the costs of development. In Europe, there is advanced harmonization in the regulatory approval of vaccines through the European Medicines Agency (EMA), and in sub-Saharan Africa, the Africa Vaccine Regulatory Forum (AVAREF) is aiming to strengthen regulatory capacity for clinical trials and harmonization of regulatory practices58.

Following all of these activities, which can take as long as ten years or more, a new vaccine is now ready for deployment, but a third hurdle can occur between the licensing of a vaccine and broad-scale implementation, which is dependent on both a policy recommendation and the ability to implement. Many years can go by before important new vaccines reach communities in need, the cost of which is measured in human lives that could have been saved as well as money for their development.

There are many contributors to this third hurdle: first is cost, which is especially relevant for countries that are neither wealthy enough to procure vaccines at high cost nor poor enough to receive funding assistance from Gavi, the Vaccine Alliance. However, when a Gavi-eligible country transitions out of the programme owing to an increase in its gross national income per capita, it needs to increasingly mobilize domestic resources or other development assistance59. Even when the broader value proposition of a new vaccine is substantial, there remains the question of affordability. Second is the question of country capacity to take on new vaccines; the past decade has been a remarkable era for vaccine introduction, with 113 countries having introduced at least one new vaccine, which represents a real success story60. Country capacity to introduce and sustain ever growing programmes involves human and financial resources, and time to build political support and community demand. Both the pneumococcal conjugate and the rotavirus vaccines now have coverage in low-income Gavi countries that meets or exceeds the global average; however, this reflects the fact that not all countries in any income strata have yet introduced these vaccines in spite of their availability61. Even high-income countries can experience delays. Thus, in the United Kingdom, a meningococcal B vaccine was licensed in January 2013, recommended for introduction in March 2014, and finally announced for introduction in May 2015. It then took more than 12 months to resolve procurement discussions to enable implementation62.

For products that address priority diseases for low-income countries, the uncertainty of the market may risk products collapsing unless a full end-to-end product solution is articulated, with non-commercial support. Inclusion of the new vaccine in the WHO’s pre-qualification list is a requirement for procurement through funders such as UNICEF and Gavi. Some of these are vaccines against parasitic diseases, which are much more complex than bacterial or viral vaccines owing to the wide range of antigens with often a complex life cycle that exhibit different antigens relevant for vaccine protection. Thus, the RTS,S vaccine—the first ever malaria vaccine used in a routine immunization system63—took nearly 30 years since its creation by GlaxoSmithKline in 198764 before the EMA issued a positive scientific opinion in 2015, and the WHO recommended large-scale pilot programmes in 2016. These programmes took another three years to start in several African countries, and demonstrate the sometimes incredibly long development, licensing, and introduction times. The RTS,S malaria vaccine is also an example of a vaccine for which the clinical trial performance of partial protection led to a policy decision to advance in a step-wise manner rather than full programmatic deployment. This may become a more common pathway for future products, in part because these vaccines have performance and implementation characteristics that are more complex than those of current vaccines.

We are entering an era in which the path from vaccine licensing to routine implementation requires more than safety and efficacy data. Policy recommendations for new vaccines may only be realized after implementation research to determine how to ensure use and impact most effectively. Deliberations about cost effectiveness, the full value of vaccine assessments, and country priorities in the face of constrained resources remain drivers for delays associated with the third hurdle. National Immunization Technical Advisory Groups (NITAGS) will be increasingly important to guide evidence-based decision making.

Even after the lengthy and costly trajectory to introduce a new vaccine, ensuring sustainable impact faces a fourth set of hurdles that need to be overcome. These include supply and demand sustainability, and resilience and acceptance of immunization. Logistical issues such as the in-country ‘cold chain’ system of transporting and storing vaccines at recommended temperatures, procurement management, and the organization of vaccination clinics in remote areas, vaccine hesitancy, and equity of access can all present challenges. In addition, the misuse of vaccination campaigns as political tools has seriously damaged vaccine confidence in areas such as the Philippines, Nigeria, Afghanistan, Italy and Pakistan65. Some side effects or limitations of duration of protection may only become obvious after larger scale use, such as for live oral rotavirus vaccination in high-mortality settings66, pertussis vaccine67 and others68. A recent example is the results from a retrospective analysis of long-term efficacy trials that show that although there is a clear overall population benefit of the Dengvaxia vaccine against dengue, the vaccine also caused an excessive risk of severe dengue in seronegative vaccinees (that is, those not exposed to dengue virus69). In the Philippines, this new risk was reported after more than 800,000 school children were vaccinated, prompting a marked reaction by the public in 201870.

Stock-out events and vaccine manufacturing capacity have been problematic for particular vaccines, even in high-income countries. Manufacturers emphasize the time needed to build and commission a factory71. Although manufacturers in middle-income country are now supplying most low-cost vaccines globally, they face low profit margins, ferocious tenders, and often unpredictable procurement schemes. More efficient and modular production technologies may enable decentralized production with lower capital costs.

Each of the four hurdles can be overcome, although the fourth one should be a continuing concern for every national immunization programme. Depending on the phase, they may require different sets of policy actors, and are sometimes a matter of policy, management and leadership, rather than money.

Throughout the development and use of vaccines, vaccine safety is an overriding concern, and requires a continuous and careful scientific and societal assessment. Safety monitoring during manufacturing typically occupies a major part of the process and costs of a vaccine, and is a key element of any vaccine programme. In specific high-income populations, such as in the elderly, personalized medicine approaches have been proposed to maximize both immunogenicity and safety in the presence of chronic conditions and changes related to older age, but large-scale applicability is still questionable at present72,73,74.