None of the seven case studies in our study examined vaccine development and there are some features of that field that are likely to contribute to faster translation from research to application than in other fields. For example, in the past, the vaccine field has had relatively low market margins and is often seen as commercially unattractive [20,21,22]. As a consequence, quite a lot of the relevant research is conducted in universities, meaning that there are many ideas around the proof-of-concept stage that are ready to go – they provide a fertile area for integration once financial or other incentives appear. Nevertheless, the development of vaccines is still sometimes reported to take, on average, over 10 years and there is often an attrition rate for vaccine candidates of about 90% or higher as they go through the various tracks [18, 23, 24].
Despite those average figures, there are at least three particular features in the context of the development of a COVID-19 vaccine that are particularly important and play across various tracks, even if they are not likely to appear in many, or any, other situations. First, there is the intense and overwhelming nature of the COVID-19 crisis that is engulfing the globe and making it the top priority for action everywhere – meaning many prioritisation decisions are a given. Second, the widespread lockdowns and social distancing are also restricting research activities generally, with many laboratories not functioning apart from those conducting work linked to COVID-19 [22]. This highly unusual situation might mean that, in the short-term at least, concentrating resources on one area does not have the usual opportunity costs of depriving other areas of resources – because they have generally been put on hold. It is therefore possible that the queues for research resources will be much less in evidence. (However, the more usual pattern could rapidly reinsert itself as the lockdowns ease.)
Third, SARS-CoV-2 is the latest of a series of coronaviruses for which research teams have been seeking vaccines [18, 21]. Therefore, various tools, such as vaccine platforms that had already been developed or new ones that were in development, can be integrated in the search for a vaccine against the new disease. Linked to this, several non-market mechanisms were developed to make better preparation for a future epidemic, including the Coalition for Epidemic Preparedness Innovations (CEPI) based in Oslo, Norway. Established in 2017, it receives funding from governments and donors such as the Bill & Melinda Gates Foundation and the Wellcome Trust [21]. In addition to funding development of 17 vaccines against five priority pathogens, CEPI also “funded programs for unknown emergent pathogens – programs for ‘Disease X’. ‘Disease X’ now has a name: COVID-19” [21].
The four approaches above for speeding things up can now be considered, alongside the matrix in Fig. 1, to analyse how things are currently being accelerated. This draws on what has already been written about the extraordinary efforts being made by a global community of scientists, healthcare industries and coordinating organisations such as WHO and CEPI since a Chinese team published the genetic sequence of SARS-CoV-2 on 11 January 2020 [23]. Working with WHO, CEPI has developed and is “continuously maintaining an overview of the global landscape of COVID-19 vaccine development” [23]. CEPI has also estimated that many billions of dollars will be needed for the successful rapid development and manufacture of one or more vaccines [25].
When considering speeding up progress on developing and delivering a COVID-19 vaccine against in each of the four groups of tracks in Fig. 1, it is immediately obvious that the concept of overlapping tracks is hugely important and facilitates the idea of working in parallel on various items. Additionally, some of the drivers of the increased speed are the overlapping action in the regulatory and reimbursement tracks towards the top of the matrix, which can potentially play a role in pulling developments through more rapidly from the lower tracks.
The CEPI team have developed a paradigm specifically for a pandemic, which they contrast with a more linear traditional paradigm for vaccine development [19]. As with our Fig. 1, the key feature of this are the phases that overlap; additionally, it includes the development of manufacturing capacity in the overlapping phases, which will be crucial for the rapid mass production of the vaccines. We had not included manufacturing capacity in our matrix as investing in sufficient capacity is generally not the limiting factor in conventional development of new medicines. Consequently, manufacturing capacity did not arise as a delaying issue in our case studies – although there was possibly a somewhat comparable situation with the lack of capacity in the form of trained cognitive behavioural therapists, until resources were found for additional training. However, given the scale of manufacture likely to be necessary for COVID-19 vaccines and the hoped-for considerably shortened timescale, it is being highlighted as an issue in current discussions [25]. The analysis below linked to our matrix throws light on how events are unfolding in a timescale that is much more rapid than previously seen.
Discovery research track
Partly through the large-scale funding provided through CEPI and others, some teams are reporting extremely rapid progress with basic preclinical/animal research; for example, a press release from Inovio, a United States company, on 6 April 2020 marking the launch of its Phase I clinical trial, stated the following: “Preclinical data, which have been shared with global regulatory authorities and submitted as part of the IND [Investigational New Drug] [application], have shown promising immune response results across multiple animal models” [26]. The company went on to say that additional preclinical studies “will continue in parallel with the Phase 1 clinical trial”. One of the keys to rapid progress, in this case with a DNA vaccine and in other cases, such as the University of Oxford’s Jenner Institute in the United Kingdom, with a vector vaccine, is that the teams had already been working on a vaccine for MERS-CoV, another coronavirus that is the causative agent for Middle East Respiratory Syndrome (MERS) [26, 27]. Gilbert explained how her team at the Jenner Institute had conducted research using improved research processes prior to the pandemic to create a new vector vaccine platform and had “started thinking about an appropriate response to Disease X; how could we mobilise and focus our resources to go more quickly than we had ever gone before. And then Disease X arrived” [27]. Gilbert is aiming to have a vaccine ready for use in Autumn 2020, a shorter timescale than any other team seems to have suggested; however, in terms of identifying the starting point of the relevant research, which is always problematic [10], her discovery research stretches back well before January 2020 [27]. A major new feature assisting the more rapid development of a vaccine now is the unprecedented level of global cooperation within the scientific community and with other relevant bodies, with, for example, scientists reporting important findings on conference calls organised by WHO rather than using time to write and publish academic papers [21, 22]. Some of the animal trials for both Inovio and the Jenner Institute are being conducted by a laboratory of Australia’s Commonwealth Scientific and Industrial Research Organisation. It pointed out that “Normally it takes about one-to-two years to get to this point and we’ve in fact shortened that to a period of a couple of months” [28]. Preclinical testing for the Jenner Institute has also been conducted in the United Kingdom and United States, with promising results reported [29].
Improved processes also have a role in reducing development time during the pandemic [21, 27]. In particular, novel platforms are being used, with those based on DNA or mRNA offering “great flexibility in terms of antigen manipulation and potential for speed” [23]. A partnership between another company, Moderna, and the United States National Institute of Allergy and Infectious Diseases (NIAID) started clinical testing of Moderna’s mRNA-based vaccine just 2 months after the announcement of the genetic sequence but initially skipped one of the stages of animal testing [28]. While the mRNA-based platform for delivering vaccines had been shown to be safe in humans, this COVID-19 vaccine had not [30], and “mRNA-1273 faces numerous challenges in clinical development and manufacture before it has the possibility of being made available for global immunization” [21]. Animal studies are usually a vital first step, required for regulatory approval.
Human research and research review tracks
Phase I, II and III – first-in-human/safety, design/dosage, efficacy
We consider these three phases as one group because different approaches use somewhat different terminology but still cover the same essential items. The CEPI analysis of the COVID-19 vaccine development landscape published on 9 April 2020 reported that, of the 78 identified vaccine candidates confirmed as active, five were in Phase I trials – the studies by Moderna and Inovio described above, plus three Chinese studies [23]. Following links in that paper reveals that all five anticipate many months of research just for Phase I, although, as reported in late April 2020, CanSino, a Chinese company developing a vector vaccine [23], was the first to move into a, presumably overlapping, Phase II study [24]. In a press release on 30 April 2020, Inovio referred to potentially advancing “to Phase 2/3 efficacy trials this summer” [31]. Vital considerations in how far the candidate vaccines will move through the trial phases and the extent of overlap will be considerations of safety and financial risk. There are suggestions that some of the usual safety procedures that could constrain progress during the trials might be relaxed, with the NIAID, which is conducting the Phase I trial of Moderna’s mRNA vaccine, reportedly arguing that “the risk of delaying the advancement of vaccines is much higher than the risk of causing illness in healthy volunteers” [30]. Moderna’s Phase I trial initially enrolled 45 volunteers in the original three dose cohorts, but later added six more cohorts [32]. On 27 April 2020, Moderna, with funding from the United States Government’s Biomedical Advanced Research and Development Authority (BARDA), submitted an Investigational New Drug application to the Food and Drugs Administration for “Phase 2 and late stage studies of mRNA-1273 if supported by safety data from the Phase 1 study” and reported, on 1 May 2020, that it had received initial feedback on the design of a 600-participant Phase II trial, which it expected to start it in the second quarter of 2020, with a 12-month follow-up [32]. This again illustrates that regular liaison with the regulatory bodies is likely to be essential during the research as new platforms, new approaches and the immense urgency of the situation all come together.
Gilbert described the importance of work at the Jenner Institute running in parallel, funded by grants from various sources and, while the preclinical research was underway, she received ethical approval for the clinical trial and conditional approval from the United Kingdom’s regulatory authority to screen volunteers for trial enrolment [27]. Furthermore, in April 2020, drawing on the safety data from their previous trials of similar vaccines, the Jenner Institute team were able to discuss with the United Kingdom regulators the basis on which they could start a combined Phase II/Phase III trial with another 5000 participants [29] in addition to the 1102 in the Phase I trial [24]. Some of the grants received by this team also helped fund initial scaling up of vaccine production using facilities in the United Kingdom and elsewhere [27, 29]. The size and speed of the human trials that the Jenner Institute is progressing reflect the confidence gained from its prior research on other vaccines and animal testing of its COVID-19 vaccine in various models [27,28,29]. The apparently smaller and more gradual Phase I trial by Moderna, and plans for its Phase II trial, perhaps reflect the greater caution that is necessary in its human trials (despite its previous work on similar vaccines) as it avoided some of the animal trials prior to being the first to conduct human trials.
Mitigating the financial risk to running phases in parallel is the additional funding being devoted to developing a vaccine, with CEPI, among others, playing a key coordinating role in distributing donations. Also accelerating progress is that any decisions about a COVID-19 vaccine are going straight to the head of any queue for decisions about, for example, resources or ethics approval. In terms of encouraging the maximum participation by commercial enterprises, some of the debates being conducted in the ‘Reimbursement/financial support’ track could be extremely important in providing incentives.
Effectiveness/post-launch research track and research review and synthesis on effectiveness and safety track
These top two tracks of human research (Fig. 1) are usually important, including when, as often happens, new interventions are developed in an area where there are already existing interventions; this may be in order to gather cost-effectiveness data to inform policy on reimbursement decisions. With the development of a vaccine for COVID-19, as there are no existing alternatives, it is extremely unlikely that such steps would be necessary before regulatory approval and reimbursement decisions about the first approved vaccine. However, they might subsequently become very important if additional vaccines are developed and approved.
Clinical and health service track and public policy and development track
Regulatory approval/first non-research use in patients and monitoring
This essential step has to occur after the safety, dosage and efficacy trials and, while there are calls for it to be completed as rapidly as possible, there are also pleas “not to cut corners” [30]. Jiang points out that vaccines for other major diseases “have a long history of safe use and were developed in line with requirements of regulatory agencies”. He has worked to develop vaccines for various coronaviruses since 2003 and describes some of the potential dangers [30]. Nevertheless, there is clearly considerable scope in the current situation for any vaccine for COVID-19 to jump, or even avoid entirely, the queues that often exist in the work of regulatory bodies. Various teams, including the Jenner Institute and Inovio, are talking about their candidate vaccine potentially being ready in later 2020 or early 2021. Some suggest it will first be made available using the speeded up or emergency use procedures that, as discussed above, the regulatory bodies are able to use in exceptional circumstances [23, 26, 33, 34]. A member of the Jenner Institute team referred to the critical importance of the principle of transparent informed consent [33]. Regulatory authorities are already beginning to work in parallel with the organisations developing candidate vaccines, so that they are fully aware of how the trials are progressing and might indicate the extent of the evidence that would be necessary for approval in this crisis situation, as noted previously with HIV/AIDS. Regulatory authorities will have crucial decisions to make in the coming months about how far they are willing to take greater risks about safety in relation to vaccine use as well as what greater risks might be taken with the health of volunteers in the trials (see above).
National policy announcement/guidelines advice
It is highly likely that such decisions on using the vaccine would already be in place when the vaccine was ready for use. Thus, whereas there can often be long delays before action is taken on this track to promote the use of an intervention, in this instance, such delays are extremely unlikely.
Reimbursement/financial support
It is to be expected that the vaccine manufacturers and healthcare systems will have worked out these arrangements before any vaccine receives regulatory approval. Thus, again, this sometimes lengthy process should be uncharacteristically unlikely to cause delays on this occasion. This is another clear example of where there are likely to be overlaps and work in parallel on many tracks. Various funding proposals are emerging and it is widely assumed that such will be the demand for a vaccine that more than one will go into mass production [34, 35]. Overlapping approaches being advocated and implemented include carrying out more research and development (R&D) through the public sector but bringing in the private sector primarily for manufacture and distribution and adopting ‘advance market commitments’ to incentivise private R&D; the first approach is being taken by the Jenner Institute. In the first few months, funding for the Jenner Institute’s COVID-19 research has come from various public and charitable sources, including the donations channelled through CEPI and direct funding from the United Kingdom public funders of health research [23, 27]. At the end of April 2020, the Jenner Institute partnered with the British–Swedish company AstraZeneca, with support from the British Government, for the development, manufacture and large-scale distribution of the vaccine on a not-for-profit basis, with only the costs of production and distribution being covered [35]. This approach is not completely novel in the vaccine space but is the largest of its kind to date – it will be interesting to see if such approaches spread to other areas of healthcare. The Moderna vaccine candidate also shows aspects of this extension of the public sector role with some of Moderna’s BARDA support being used to develop manufacturing capacity in the United States, through collaboration with Lonza US (part of Swiss-based Lonza), which will complement Moderna’s existing more limited United States manufacturing capacity. It is aiming to start production prior to the completion of trials and scaling global production to a billion doses per year [32].
Related to the second approach of ‘advance market commitments’, Silverman et al. describe how, in terms of increasing the speed of development of vaccines, the supply-side investments in R&D are the pressing issues but that getting the demand-side right is also important [36]. In contrast to the Jenner Institute model, they claim that if society wishes industry to invest up-front in the risky, high-cost business of vaccine development, it might need “to offer the promise of a predictable market for an effective vaccine that offers both access for all and a reasonable return on investment – de-risking market (commercial) uncertainty while still expecting companies to absorb the scientific risk that their products will fail”. They also illustrate the considerable commercial risks that companies have faced when developing vaccines, including against previous coronaviruses. In that context, they propose that the ‘market-driven value-based advanced commitment’ is the best option as it “differentiates price according to efficacy, so incentivizing development and use of vaccines with higher rates of disease prevention”, but could also ensure vaccines were available at manufacturing cost for low-income countries [36]. This illustrates how, in this extreme situation, ensuring a credible promise of sufficient resources being available is likely to play an important role across the various tracks in the development of a vaccine.
Clinical practice track
Given the enormous health and economic burden being caused by COVID-19, it is reasonable to assume that, in contrast to what often happens [11, 14], there will be no delay from healthcare professionals in starting to give the vaccine to populations as soon as regulatory approval is secured and manufacturing capacity has geared up. CEPI has called for “funding to support global COVID-19 vaccine development efforts guided by three imperatives: speed, manufacture and deployment at scale, and global access” [23]. Questions about equity in deciding who receives the vaccines, and who receives them first, are of huge importance, but they are beyond the scope of this Commentary, which focuses on the time between starting research and the application of the intervention as a standard procedure within clinical practice in at least some countries. However, as noted above, some approaches can incentivise innovation while also encouraging a more equitable distribution than might otherwise occur.