Treatments and a vaccine for COVID-19: The need for coordinating policies on R&D, manufacturing and access

 Ten vaccine candidates were in clinical trials by May 2020 and many more were in pre‑clinical stages

As of 26 May, at least ten vaccine candidates were in clinical trials (see Table 1). Five candidates were in phase 1 trials and five candidate in combined phase 1 and 2 trials. The first phase 1 trial1 is expected to be completed before the end of 2020. In addition, as many as 160 candidates were estimated to be in exploratory and pre-clinical R&D phases (LSHTM Vaccine Centre, 2020[1]), which precede clinical trials. The number of candidates under investigation is increasing rapidly.

Vaccines can be of different types or “platforms”, described in Table 2. The various platforms have both advantages and disadvantages, and affect the expected duration of R&D and manufacturing processes. Nucleic acid vaccines deliver genetic instructions (in the form of DNA or RNA) coding for a viral protein that prompts an immune response. The nucleic acid is inserted into the host’s cells, which then produces copies of the virus protein. These vaccines are safe and easy to develop and their production only involves producing genetic material. Yet, they are still unproven since no human vaccine approved for marketing so far relies on this platform. Recombinant protein vaccines are made of viral proteins, produced by genetic engineering, which are intended to stimulate the host’s immunity. In order to work, these vaccines may require multiple doses and the use of adjuvants, which are immune stimulating molecules delivered alongside the vaccine. Viral-vector vaccines use a genetically engineered virus (such as an adenovirus) to produce proteins of the targeted virus in the body of the host. These viruses are weakened so they cannot cause disease. Viral-vector vaccines tend to be safe and provoke a strong immune response but existing immunity against the viral vector can reduce their efficacy. Finally, live attenuated and inactivated virus vaccines use the virus itself, in a weakened (attenuated) or inactivated form, to generate immunity. Many existing vaccines are made in this way today, such as those against measles and influenza, but they require extensive safety testing.

The SARS‑CoV‑2 vaccine platforms currently in phase 1 and 2 clinical trials are nucleic acid vaccines, including DNA and messenger RNA (mRNA, an intermediary between DNA and proteins), viral vector-based vaccines and inactivated vaccines. Candidates currently in pre-clinical R&D also include recombinant protein and live-attenuated vaccines and modifications of vaccines that have already been tested against other diseases, such as measles.

 However, a vaccine may not be widely available for months or years from now

Based on information currently available, reasonable estimates of the time it will take for a vaccine for SARS‑CoV‑2 to become available range anywhere from 12/18 months to several years. The assumption that a vaccine could be widely available within months is optimistic and would be much faster than the historical average time of 6 to 9 years for the completion of the clinical development of a novel vaccine (see Box 1).

Development of vaccine candidates for SARS‑CoV‑2 has started at breakneck speed in 2020. Estimates on the optimistic end of the range assume that one of the candidates already in clinical trials will turn out to be safe and effective. For a number of reasons, development might indeed be quicker than usual.

• First, the genetic information of viruses can be sequenced much faster than before and SARS‑CoV‑2 is genetically similar to coronaviruses subject to prior research, so vaccine research and development does not start from scratch.

• Second, a large number of candidates are being tested in parallel, using different platforms, which increases the chances that at least one might be successful.

• Third, some types of candidates in development rely on a new platform: messenger nucleic acid vaccines (mRNA), which have great potential for rapid development (see, Tables 1 and 2 and Thanh Le et al. (2020[1])). Others may build on existing vaccines or candidates in development for other diseases, so some relevant evidence of safety data may already be available.

• Fourth, the current pandemic makes development urgent. This could be leading to faster development processes, for instance through shorter clinical trials, running trials in parallel that are usually done sequentially, and faster regulatory approval.

However, there are also limits to accelerating the clinical development process and acceleration cannot come at the expense of safety. Safety standards have to be high for vaccines and treatments, and particularly for vaccines because they are injected into a large number of healthy people (Jiang, 2020[6]). There thus has to be robust evidence that their benefits outweigh the risks. Knowledge about immunity is still limited. Inducing a desired immune response against SARS‑CoV‑2 might be particularly challenging because of the risk of harmful inflammatory and autoimmune reactions (Iwasaki and Yang, 2020[7]). Given the uncertainties, it is very difficult to estimate with more precision how long it will take for an effective and safe vaccine to become available.

It will take at least 12 to 18 months for an effective #vaccine against #COVID19 to become widely available, and only if current clinical trials turn out to be successful

 New pull mechanisms should complement existing push mechanisms and more co‑ordination is needed to complete promising R&D projects

A combination of push and pull mechanisms are needed to complete development of a vaccine, not only to respond to the current pandemic but also to prepare for potential future disease outbreaks. They should be designed to help ensure that the R&D projects that are currently in early clinical phases are brought all the way to successful conclusion and not abandoned once the immediate urgency of the pandemic has subsided. Issues around the sustainability of R&D funding have been reported for prior disease outbreaks. For instance, the vaccine R&D projects launched after the outbreak of SARS-CoV‑1 in 2003 were abandoned before successful completion due to a lack of resources. This is despite the availability of a number of promising candidates and awareness of the risk these pose on humans (Chen et al., 2020[20]; Menachery et al., 2015[21]).3 Had these been completed at the time, it would have given current R&D on SARS‑CoV‑2 vaccines a head start. Completion of current vaccine development might also have relevance beyond response to the current pandemic if COVID‑19 turns into a seasonal illness, similar to influenza.

Push mechanisms, such as research grants, ensure that R&D is conducted but are not conditional on a specific outcome. While they are an effective means of kick-starting early stage R&D, they do not provide incentives for completing R&D through expensive late-stage phases and bringing new products to market. Pull mechanisms can overcome some of these problems by rewarding successful completion of clinical trials, getting a product approved for marketing by regulatory agencies, or delivering a specified quantity of an approved product. They can harness competition and can be more efficient than push mechanisms, by incentivising private investors to “enter a race” for developing and producing effective health technologies. Examples of pull mechanisms are when governments or philanthropists commit to awarding a prize to the first firm or research institution to develop a new product, or guarantee the purchase of a specified volume of a new vaccines once it has been shown to be effective and is approved by regulatory agencies. Public and private not-for-profit funding play a significant role in catalysing progress in R&D towards vaccines (see Box 2) and towards new medicines for infectious diseases (Kremer, 2004[13]). But pull mechanisms require significant financial commitments to be effective. Push and pull mechanisms are discussed below.

The Coalition for Epidemic Preparedness Innovations (CEPI), a public‑private partnership that funds vaccine R&D and to which governments of several OECD countries already contribute, estimates that USD 2 billion will be required to complete R&D of an effective vaccine for SARS‑CoV‑2. CEPI has raised just over USD 1 billion by 26 May.4 A plethora of other entities have pledged funding, including various governments of OECD countries, non-governmental organisations and the pharmaceutical industry. On 24 April, the WHO launched the Access to COVID‑19 Tools (ACT) Accelerator, a global collaboration between public and private entities to accelerate not only R&D but also to ensure equitable global access to safe and effective COVID‑19 diagnostics, treatments and vaccines.5 The Coronavirus Global Response led by the European Commission has so far raised EUR 9.8 billion in funding, including pledges by many OECD countries, to support WHO ACT, CEPI and other efforts.6

With the vast amounts of funding that have been pledged, efficient ways of allocating resources have to be found by striking the right balance between an approach of “letting a thousand flowers bloom” in R&D, on the one hand, and more co-ordination and co-operation, on the other. There are various mechanisms to allocate public or non-profit funding, some of which help “de-risk” investments to attract private for-profit capital.

At an early stage, many disparate projects increase the chances of success. This is because most vaccine and drug candidates are expected to fail so the chances of success of any single candidate is low. In-vitro research, early-stage laboratory studies and small clinical trials are also relatively inexpensive compared to larger trials later on. As R&D progresses and clinical trials become larger and more expensive, it makes more sense to co-operate, pool resources and allocate them to the most promising projects. As discussed below, the amount of money necessary for an effective pull mechanism for a SARS‑CoV‑2 vaccine could well be beyond the funding capacity of a single national government. International co-operation could make the amounts committed large enough for such a mechanism to be effective.

 Manufacturing capacity has to be built while R&D is underway

Once a vaccine that is safe and effective has been developed, it needs to be manufactured at scale. Although it is difficult at this stage to estimate with any precision the number of doses that will have to be produced and delivered to populations over a short period of time, billions of doses will likely be necessary and their manufacture and distribution will be a formidable task. It is of course still unknown how many doses of a future vaccine will have to be administered for the human body to build immunity. Multiple doses may be needed for the same individual, should the vaccine require boosts to be effective.

Little information about vaccine manufacturing capacity is publicly available. However, experience from prior efforts to monitor capacity to manufacture influenza vaccines indicates that production cannot be scaled up rapidly. Vaccine manufacturing tends to be technically more complicated than producing medicines and requires a broad range of technology, human resources and quality controls (Smith, Lipsitch and Almond, 2011[23]; UNIDO and WHO, 2017[24]). Building manufacturing lines requires sustained investment and has, in the past, taken several years (UNIDO and WHO, 2017[24]). In 2015, there was global capacity to manufacture approximately 6 billion doses of influenza vaccines in case of a pandemic, sufficient for immunising about 40% of the global population with two doses (McLean et al., 2016[25]). But this capacity is only available because the same manufacturing sites produce already some 1.5 billion doses of seasonal influenza vaccinations every year (ibid.). This illustrates that, even with well-prepared capacity, it takes time to scale up production.

Countries therefore need to co-operate now to project demand and plan the necessary capacity to produce doses in sufficient quantities. While attention has so far focused on spurring R&D, there has been little co-ordination or co-operation between countries in funding, planning and building manufacturing capacity. Because it takes time to build capacity, this effort has to start now, while R&D is still underway. CEPI is already considering manufacturing capacity in its projections of funding needs.10 Several large pharmaceutical firms have recently announced that they are starting to build manufacturing capacity for future vaccine candidates, some with backing by public funders.

Capacity will have to be funded, at least partly, from public sources because uncertainty is still too high to rely only on private investment. As discussed in Box 3, an international AMC that is large enough could provide incentives for the private sector to invest not only in R&D but also in manufacturing capacity, to complement direct public funding of capacity. Alternatively, countries could also co-operate to fund the entire needed capacity directly, and separate from incentives for R&D. One source of uncertainty is that it is still unknown which of the vaccine platforms currently in trials, discussed above, will turn out to be successful. Different manufacturing challenges are associated with each vaccine platform and production lines cannot manufacture all platforms (Smith, Lipsitch and Almond, 2011[23]). If a future vaccine is based on a platform that is already used for other authorised vaccines, existing capacity can be repurposed and expanded. However, this may, in turn, create capacity bottlenecks for vaccines against other diseases. Completely new production infrastructure, however, will have to be built for new vaccine platforms, such as DNA and mRNA vaccines. Another source of uncertainty is that it is not known when a vaccine will be authorised for marketing and how big the market will be at that point. The longer it takes to complete R&D, the smaller the market for a vaccine may become, as more and more people get infected and possibly build immunity and as societies adapt to living with an endemic virus.

 Treatments tested so far have provided disappointing results

Most of the clinical trials underway by May 2020 are testing treatments. Rather than coming up with compounds from scratch that may take years to develop and test, researchers are currently mainly looking to repurpose medicines already approved for other diseases and known to already have a positive benefit/risk balance for conditions other than COVID‑19. They are also looking at unapproved drug candidates that have performed well in pre-clinical studies with the past two deadly outbreaks of coronaviruses between in 2002 and 2012, which caused severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) respectively.

Given the current state of knowledge and limited progress so far, expectations that treatments will become game changers in the fight against SARS‑CoV‑2 need to be tempered. The drug candidates currently being tested have potential to improve the clinical management of patients with COVID‑19 but do not provide a cure and are unlikely to be used to prevent people from getting sick. As of 26 May, there is no evidence from randomised controlled trials (RCTs) that any potential therapy under investigation improves outcomes in patients with either suspected or confirmed COVID‑19. Most of them are associated with significant side effects and target narrow patient groups, such as the most severe cases. Also, some of them can only be administered intravenously, limiting their use to hospital settings.

With more than 500 clinical trials of treatments currently underway (Thorlund et al., 2020[27]), including the large-scale trials “Solidarity” and “Discovery”,11 the state of knowledge will evolve rapidly. International co-ordination is needed to ensure that clinical trials are well-designed, adhere to common methodological standards and are sufficiently large to yield conclusive information. This has not always been the case across the hundreds of trials in the COVID‑19 R&D effort so far, which included many disparate and small-scale trials of the same treatments (Mullard, 2020[28]; Thorlund et al., 2020[27]). The controversies around hydroxychloroquine and chloroquine and the current uncertainty around the effects of remdesivir are examples of how small-scale trials can cause confusion (Nature, 2020[29]). Some innovative approaches are emerging to ensure high standards of research in the context of the epidemic. For example, the REMAP-CAP study tests a variety of treatments against COVID‑19. It will include participants from more than 160 sites across 14 countries. Sophisticated clinical trial designs allow researchers to add treatments to the trial as it is running, and to remove those for which data indicate that they are not performing well. REMAP-CAP was originally designed to study pneumonia and has now refocused on COVID‑19 (ibid.).

Table 3 contains an overview of COVID‑19 treatments being assessed as of 26 May that have attracted the most attention and are being considered the most promising. The different strategies being tested try to tackle the infection at three different steps of its natural history:

• Prevent the virus from getting into the host’s cells; this is the case of chloroquine/hydroxychloroquine and antibody-based treatments made from convalescent plasma;

• Prevent the virus from replicating once inside the host’s cell; this is how most antivirals act;

• Prevent the over-reaction of the immune system to the infection (the so-called “cytokine storm”, which is responsible of the severe cases of COVID‑19 infections); this is the case of some immunosuppressive treatments

Eventually, the treatments currently tested may contribute to building some sort of a “tool box”, from which doctors would choose to manage patients on a case by case basis. Emergency measures such as the Emergency Use Authorization (EUA) of the US Food and Drug Administration (FDA) may contribute to accelerating approvals but phase 3 double-blind randomised controlled trials (the gold standard in medical investigation) take several months. Despite the urgency, exceptional circumstances should not be a reason for authorising treatments that cause more harm than benefit (London and Kimmelman, 2020[8]).

 Policy also needs to ensure that effective treatments will be widely available

Medicines go through stages between discovery and delivery to patients that are similar to vaccines, as illustrated in Figure 1. However, there are some important differences. Most importantly, medicines are only given to people who are already infected with SARS‑CoV‑2 and usually target specified patient groups, such as severe and critical cases. The product volume to be manufactured may therefore be smaller than in the case of vaccines. While it is difficult to find chemical compounds that are effective in treating a disease, medicines made of chemical ingredients are relatively cheap and straightforward to manufacture.

Nevertheless, pharmaceutical supply chains may not be prepared for supplying sufficient volumes of treatments during a pandemic. Even if some medicines are relatively straightforward to manufacture, their production frequently relies on rare chemical ingredients that can only be procured from a small number of suppliers. Supply chains can be complex and it is enough that one critical input is in short supply for production to grind to a halt (Ledford, 2020[30]). The high and increasing number of medicine shortages reported in recent years in OECD countries12 is an indicator of an already tense situation in this industrial sector and health emergencies, such as the ongoing pandemic, adds to the risk of shortages (Ledford, 2020[31]).

Policy also needs to ensure that there will be sufficient capacity to manufacture effective medicines at scale and that products will be widely accessible. This includes providing the right incentives to manufacturers and building the necessary capacity in global supply chains. Most importantly, policy needs to ensure that medicines will be accessible to those in need and that pricing and barriers to international trade do not constitute barriers to access. This is discussed in the next section.

 Intellectual property rights incentivise R&D and there are various ways to ensure affordability of health technologies

In the current rush for finding a way out of the public health crisis, financial incentives for R&D need to be reconciled with affordability and equity concerns. Usually, pharmaceutical R&D mainly relies on various forms of intellectual property rights (IPRs) to incentivise private investment. Patents, in particular, are critical for incentivising R&D. They also favour the dissemination of new knowledge because they require disclosure.13 While critical for incentivising R&D, IPRs give their owners market power to limit supply and obtain high prices, which can create barriers to broad access to health technologies. In the context of COVID‑19, vast amounts of public funding have already allocated to R&D and, as argued above, more funding will be needed. Given that taxpayers already bear much of the risk and costs of R&D and that broad access to a new vaccine and effective treatments will be key to restoring social and economic life, IPRs should not create financial access barriers and product prices will need to be close to the cost of production to ensure affordability. How countries share the cost of R&D and production will mainly depend on the contributions respective governments make to funding push and pull mechanisms for R&D and manufacturing.

 Countries need to agree how to distribute new vaccines to avoid future trade disputes and bidding wars

Upfront agreements among countries on how to allocate scarce product volumes are necessary. This is to avoid potential unilateral action by some countries, including panic-buying and excessive stockpiling and export bans by producing countries. Such behaviour has occurred in the past, for instance in the 2009 influenza pandemic.23

Procurement schemes based upon international co-operation need to be defined upfront and have to identify a criterion for allocating product volumes to countries that is not based on the ability to pay. Countries could, for example, agree that those hit hardest by the pandemic will have priority access to vaccines. Volumes could also be allocated according to population size, with each country receiving a share of vaccines that is proportionate to its share of the total population of the countries that co-operate, or according to the size of population groups that are particularly high-risk, such as the elderly and people with chronic diseases. Given the global scale of the pandemic, co-operation would have to be broad, involving as many countries as possible.

An agreement could also comprise a broader commitment to trade in medical supplies. Multilateral discussions on facilitating cross-border flows of vital medical supplies and other essential goods and services are already underway, including proposals on eliminating tariffs on these products. For instance, on 5 May, 44 WTO Members circulated a statement on COVID‑19 and the multilateral trading system committing to “encourage work at the WTO on concrete actions aimed at facilitating cross-border flows of vital medical supplies and other essential goods and services, including through the application of best practices and simplified procedures and through further trade opening.”24 Concrete proposals have been made by New Zealand and Singapore for a “Declaration on Trade in Essential Goods for Combating the COVID‑19 Pandemic” (WTO, 2020 G/C/W/777).25 It provides a list of critical goods and proposes, among other things, tariff elimination, restrictions on export prohibitions, intensified consultations on non-tariff barriers, and greater facilitation of trade.

Experiences from existing international joint procurement schemes can provide lessons to countries on how to plan demand for a vaccine ex-ante and put co-operation into practice. Procurement comprises the entire process of acquisition of supplies at specified prices, and at recognised standards of quality, involving a wide range of activities including price negotiations, demand forecasting, budgeting, and timely delivery (Management Sciences for Health, 2012[30]). Prior examples of international co-operation in procurement range from loose arrangements of information sharing to more integrated forms, where participating countries may open joint tenders, enter into contracts jointly or set up a central buying unit that enters into economic transactions with suppliers (World Health Organization, 2016[31]).

For instance, the Pan American Health Organization (PAHO) Revolving Fund for Vaccine Procurement established in 1979 is a joint procurement scheme that now comprises 41 Latin American and Caribbean countries (World Health Organization, 2016[31]; DeRoeck et al., 2006[32]). The Revolving Fund represents a high level of integration, with tendering, contracting and payment performed centrally by PAHO. A more recent example comes from Europe. The EU is now making use of the Joint Procurement Mechanism26 established in the aftermath of the H1N1 influenza pandemic to deal with the COVID‑19 crisis. This sets a joint procurement procedure to purchase vaccines, antivirals and other medical supplies, including medical devices and other goods or services aimed “at combating serious cross-border threats to health” (European Commission, 2016[33]). As of April 2020, 36 countries have signed this, including all EU and EEA countries, as well as the United Kingdom, Albania, Montenegro, North Macedonia, Serbia and Bosnia and Herzegovina. This mechanism represents a high degree of integration between participating member countries in that the European Commission takes central responsibility for the procurement process, opens tenders on behalf of countries, becomes the sole contractual counter party for suppliers and allocates products to member countries (ibid.). However, there is no requirement for exclusivity and member states can continue to contract individually with suppliers while participating in the scheme; they are also allowed to opt out of the scheme at any stage (Azzopardi-Muscat, Schroder-Beck and Brand, 2016[34]).