International Monetary Fund A crisis like no other, an uncertain recovery.
Although the spread of the virus can be mitigated through physical distancing, face coverings, and testing and tracing—and potentially with therapeutics—the risk of outbreaks and disruption to economic and social life will probably remain until effective vaccines are administered to large portions of the global population to prevent hospitalisation and severe disease, and preferably achieve herd immunity to halt transmission of the virus.
Several COVID-19 vaccines have now been authorised or approved for human use, with many more in the late stages of clinical development. Yet having licensed vaccines is not enough to achieve global control of COVID-19: they also need to be produced at scale, priced affordably, allocated globally so that they are available where needed, and widely deployed in local communities (figure 1). These four dimensions of the global vaccination challenge are closely related, and the development and production steps have important implications for pricing, allocation, and public confidence.
In this Health Policy paper, we review potential challenges to success in each of these dimensions and discuss policy implications. To guide our review, we developed a dashboard (figure 2) to highlight the key characteristics of 26 leading vaccine candidates, based on the target product profiles for COVID-19 vaccines set by WHO.
WHO Target product profiles for COVID-19 vaccines, version 3.
We focused on characteristics that distinguish individual vaccine candidates from one another. We used a traffic-light system to signal the potential contributions of each candidate to achieving global vaccine immunity, with the colour red indicating high risks to achieving widespread immunity, amber indicating medium risk, and green indicating little or no risk. Appendix 1 outlines the methodology for constructing the dashboard, including the criteria for assigning a green, amber, or red light for each characteristic. Although specific datapoints and their corresponding traffic-light categorisations are subject to change as the pandemic response progresses, the dashboard will continue to provide a useful lens through which to analyse the key issues affecting the use of COVID-19 vaccines.
Development and production
Several manufacturers have successfully developed COVID-19 vaccines in less than 12 months—an extraordinary achievement, given it typically takes a decade or longer to develop new vaccines.
but that has not been the case in this pandemic. As of Feb 3, 2021, there were 289 experimental COVID-19 vaccines in development, 66 of which were in different phases of clinical testing, including 20 in phase 3. Only five of these 66 vaccines—those developed by AstraZeneca in partnership with Oxford University, BioNTech in partnership with Pfizer, Gamaleya, Moderna, and Sinopharm in partnership with the Beijing Institute—have been authorised by stringent regulatory authorities (as per WHO criteria of such authorities
WHO List of stringent regulatory authorities (SRAs).
) or WHO (figure 2). Another five—from China, India, Kazakhstan, and Russia—have received approval or been authorised for emergency use by other regulatory agencies; some of the organisations developing these vaccines have submitted documentation to WHO for emergency use listing or prequalification, but these submissions are still under review.
WHO Status of COVID-19 Vaccines within WHO EUL/PQ evaluation process.
Additional vaccines from Novavax and Johnson & Johnson are expected to be authorised on the basis of positive interim phase 3 results. Several vaccines have shown high levels of efficacy (ie, more than 70%) in clinical trials, although not all developers have published their results; most of the authorised vaccines have been shown to provide strong protection against hospitalisations and deaths due to COVID-19.
Whereas public support for basic research and early-stage drug development is widespread,
Contribution of NIH funding to new drug approvals 2010–16.
the urgent need to develop COVID-19 vaccines and scale up supply has inspired new ways of aiding research, development, and production activities and enlisting broad participation among private companies.
Governments and non-profit organisations have financed clinical trials, invested in the building and expansion of production facilities, and established contract manufacturing and distribution networks to enable the rapid roll-out of successful vaccines.
The table summarises publicly available data on investments by governments and non-profit organisations into the research, development, and production of advanced COVID-19 vaccine candidates (appendix 2). In total, developers have received approximately $10 billion in public and non-profit funding for their vaccine candidates, although this number is probably an underestimate, given the scarcity of data on some of these projects. The top five companies have each received between $957 million and $2·1 billion in funding commitments, mostly from the US Government and the Coalition for Epidemic Preparedness Innovations (CEPI). The Chinese and Russian Governments have invested in several vaccine candidates being developed by private companies or state-owned enterprises. Because many funding arrangements are confidential, details regarding the specific breakdown of spending are unclear.
TablePublic and non-profit funding for the research, development, and production of leading vaccine candidates
Data are as of Feb 3, 2021. The sources and methodology are outlined in appendix 2, which also includes more information about the funding arrangements. In brief, for developers with COVID-19 vaccines that have been approved or authorised for human use in one or more countries, are in phase 3 clinical testing, or are under contract with CEPI or the COVAX Facility, we searched press releases from developers and funders, as well as financial reports filed by developers with regulators in various countries, for information on public and non-profit funding. We did not count funds provided to licensees that produce and distribute vaccines on behalf of lead developers or to contract development and manufacturing organisations, nor did we count loans (ie, debt financing) from international financial institutions (eg, European Investment Bank) or national governments. We included pre-purchase agreements between governments and companies where it appeared as though a substantial portion of the funding went towards late-stage development (ie, phase 1–3 trials) or scaling up production at risk before the completion of clinical testing. CAMS=Chinese Academy of Medical Sciences. CEPI=Coalition for Epidemic Preparedness Innovation. IMB=Institute of Medical Biology (China). RIBSP=Research Institute for Biological Safety Problems (Kazakhstan). SII=Serum Institute of India.
Attention has now turned to expanding production capacity to promote the widespread roll-out of successful vaccines, as well as efficiently distributing them to administration facilities. Companies with leading candidates have reported widely different supply capabilities up to the end of 2021 (figure 2). Nine developers have said they will be able to produce at most 700 million doses each this year, while ten other manufacturers have set production targets of 1 billion doses each or more. No single company will be able to supply all countries in this period, even if they meet these estimated production figures.
Scaling up production to meet global demand is a monumental challenge.
Global, regional, and national estimates of target population sizes for covid-19 vaccination: descriptive study.
Before this pandemic, there were no existing networks of contract manufacturers for several of the leading vaccine candidates that feature novel technologies, including those relying on mRNA delivery platforms. Additionally, the volume of vaccines that is needed places pressure on global supply chains for inputs, such as glass vials, syringes, and stabilising agents.
The production of COVID-19 vaccines is limited by the highly concentrated state of global vaccine manufacturing capacity,
Coalition for Epidemic Preparedness Innovations Manufacturing survey results analysis.
and the relationships established between lead developers and contract manufacturers. A successful solution to the production bottleneck would probably require widespread technology transfer to enable the expansion of manufacturing capacity. Currently, few countries have the domestic capacity to rapidly produce COVID-19 vaccines on their own and instead will need companies to actively share knowledge, technology, and data with domestic manufacturers.
Knowledge transfer for large-scale vaccine manufacturing.
Some of the lead developers of COVID-19 vaccines have collaboration agreements with manufacturers in middle-income countries—AstraZeneca has such agreements with the Serum Institute of India, Fiocruz in Brazil, mAbxience Buenos Aires in Argentina, and Siam Bioscience in Thailand; Johnson & Johnson has an agreement with Aspen Pharmacare in South Africa; and Novavax with the Serum Institute of India—although the terms of these partnerships, including the extent to which the licensed manufacturers can negotiate their own supply arrangements with countries, are unclear.
Many commentators have called for a cooperative approach to vaccine allocation and deployment.
The tragedy of vaccine nationalism. Foreign Affairs.
In doing so, appeals to values of fairness and solidarity are common. By contrast, the widespread disregard for a global approach to vaccine allocation shown by national governments misses an opportunity to maximise the common good by reducing the global death toll,
The tragedy of vaccine nationalism. Foreign Affairs.
More equitable distribution of COVID-19 vaccines would help contain the pandemic sooner, and thus minimise the risk of new variants of the virus arising, against which existing vaccines might be less effective.
In this Health Policy paper, we have stressed the interactions among the four dimensions involved in the global COVID-19 vaccination challenge. It is not enough to have new vaccines developed; they must be affordable, accessible, trusted, and, to maximise impact, used efficiently.
Governments and other vaccine purchasers must now decide which vaccines to procure, as well as how to secure funding for COVID-19 vaccines and vaccination programmes. To reach these decisions, government officials and partners in international organisations will need to assess the suitability of various vaccines for their respective health systems and populations—for example, in terms of availability, affordability, efficacy, and dosing and storage requirements.
The dashboard highlights the trade-offs associated with leading COVID-19 vaccines in relation to these dimensions (figure 2). Multiple vaccines, for instance, are highly efficacious—exceeding WHO targets of a minimum of 50% and preferably 70% efficacy—but require ultra-cold storage during transport or have little reserved capacity for low-income and middle-income countries. Although all currently authorised or approved vaccines require two doses, single-dose vaccines that can be stored at refrigerated temperatures are in the late stages of clinical development, with one by Johnson & Johnson likely to be authorised; these vaccines would be easier to deploy in resource-constrained settings, which might lack infrastructure for delivering and administering two-dose vaccines reliably.
Differences in product characteristics might become particularly salient in 2021, while vaccines remain in short supply. If additional vaccines are successful in clinical testing and developers meet their production targets, then COVAX could allocate vaccines, in part, on the basis of their suitability for local conditions. For instance, should single-dose vaccines that can be stored in refrigerators become available, which seems increasingly likely given the promising interim results by Johnson & Johnson, then these could be prioritised for distribution in low-income and middle-income countries that lack ultra-cold supply chains or national vaccine registries for two-dose regimens.
The dynamics of production and development have important implications for each of the other dimensions. Governments and non-profit groups have committed unprecedented sums towards the development of COVID-19 vaccines and the infrastructure to produce them at scale, which has helped companies develop new vaccines in record time. But affordability remains a concern, given the volume of doses that countries will need to purchase and the additional expenditures that distributing and delivering vaccines entails. The extensive involvement of public funders in the development and production of COVID-19 vaccines provides them with opportunities to make these vaccines globally affordable. External funders that have invested in companies developing the vaccines and who share the financial risks could try to influence the pricing of these products, as CEPI has aimed to do with uncertain levels of success.
Coalition for Epidemic Preparedness Innovations Summary of equitable access provisions in CEPI’s COVID-19 vaccine development agreements.
Funders could also negotiate clear timelines for the recovery of research, development, and production costs by companies; for example, initial doses might be sold at higher prices in the first year in high-income countries and then sold closer to their marginal cost in subsequent years.
Advance market commitments for vaccines against neglected diseases: estimating costs and effectiveness.
Determining these prices will require governments to audit the financial records of vaccine makers.
These allocation challenges also relate to production: conflicts over priority access to scarce vaccine doses could be made less acute with greater output (ie, with reduced scarcity of vaccine doses). To that end, WHO has called for member states, manufacturers, and other organisations to commit to sharing knowledge, intellectual property, and data related to COVID-19 health technologies, through the COVID-19 Technology Access Pool (C-TAP). Similarly, several countries have proposed to suspend World Trade Organization rules on intellectual property rights during the pandemic, suggesting that doing so could facilitate scale-up. Yet, as of February, 2021, no manufacturers of leading vaccine candidates have engaged with C-TAP, and the World Trade Organisation reform proposal has not gained traction.
In this domain too, the extensive public role in funding vaccine development potentially provides opportunities. Funders could encourage vaccine developers receiving public support to share their technologies and know-how systematically and widely to expand global production. Funders could also work with developers to alleviate supply chain constraints and accelerate the scaling up of production. To the extent that international control of COVID-19 is regarded as a priority for individual countries, governments might have an incentive to exercise these levers.
Public confidence and trust in COVID-19 vaccines and those who deliver them to ensure uptake are as important as the vaccines’ safety, efficacy, and affordability. Policy makers should urgently engage with communities to improve confidence in vaccines and combat misinformation and rumours around COVID-19. Post-marketing surveillance is important to build confidence during vaccine roll-out. Developing successful, locally tailored strategies requires an understanding of contextual and historical influences of vaccine hesitancy and refusal.
Risk in vaccine research and development quantified.
Equally, vaccine manufacturers should aim for maximum transparency and scrutiny of their clinical trial data to build public trust. Regulatory bodies safeguard public health by assessing whether the benefits of pharmaceuticals outweigh their risks. Regulatory decisions and their rationale should be clearly communicated to the public to provide reassurance that authorised products are safe and efficacious. It is in the interest of vaccine developers to seek approval or emergency use authorisation from a stringent regulatory body or WHO: only vaccines that have gone through one of these regulatory pathways will be eligible for purchase through COVAX or through funds made available by major development banks.
MS-K reports receiving grants from Health Action International, outside the submitted work. AJP is Chair of the UK Department of Health & Social Care’s Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in policy advice on coronavirus vaccines. He is also a member of the WHO Strategic Advisory Group of Experts (SAGE) and Chief Investigator of the clinical trials for vaccine candidate AZD1222 against COVID-19, sponsored by the University of Oxford. The University of Oxford has entered into a partnership with AstraZeneca on vaccine development for candidate AZD1222. The trials are funded by UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), the Coalition for Epidemic Preparedness Innovations (CEPI), the National Institute for Health Research (NIHR), the NIHR Oxford Biomedical Research Centre, and the German Center for Infection Research (DZIF). HJL reports receiving grants from Merck and GlaxoSmithKline, and honoraria from Merck (for serving on a vaccine confidence advisory board) and GlaxoSmithKline (for speaking at staff training sessions). MJ reports receiving grants from the Bill & Melinda Gates Foundation (INV-016832), European Commission’s Horizon 2020 programme (101003688), and National Institute for Health Research (NIHR200929, NIHR200908), outside the submitted work. All other authors declare no competing interests.
OJW, KCS, and MJ conceived of and designed the manuscript. OJW and MS-K collected and analysed the data. OJW drafted the manuscript. All authors had full access to all the data in the study, contributed to revisions to the article, and had final responsibility for the decision to submit for publication.