It is hard to predict when vaccines against infection by SARS-CoV-2 coronavirus may become available. The emergence of COVID-19 has led people to think that the best way of preventing it will be by using vaccines, as normally occurs when a new infectious disease appears. News items are published continuously in the general media which state that vaccines will arrive in a few months; however, there are relatively few papers in the scientific press about this subject.
There is clearly great interest in producing vaccines against this disease, and many companies and academic institutions around the world are working to achieve this. The informative draft supplied by the World Health Organisation (WHO) and updated on 11 April lists 70 candidate products for vaccines that are under evaluation: 3 vaccines that are being clinically evaluated, and 67 which are in preclinical evaluation. The majority of these products are under development in basic research laboratories; if they pass the first phases, they will have to be transferred to pharmaceutical industries which have the capacity to perform the clinical trials that are necessary to guarantee their efficacy and safety, with the necessary scale of manufacturing capacity to supply the vaccines to the populations that need them. Rather than months, the timescale involved in achieving this is normally counted in years. Nevertheless, the enormous humanitarian and economic impact of the COVID-19 pandemic is driving the evaluation of next generation vaccine technology platforms, using new paradigms to accelerate development. In fact, clinical evaluation of the first candidate vaccines commenced with unprecedented swiftness on 16 March 2020, taking into account the fact that the SARS-CoV-2 genetic sequence was published on 11 January 2020. This is why different international medical bodies estimate that 12-18 months will be required before a SARS-CoV-2 vaccine is available.
Is it possible to coordinate efforts to speed up progress in obtaining vaccines against COVID-19?The Coalition for Epidemic Preparedness Innovations (CEPI), an alliance founded in Davos in 2017 by the Indian and Norwegian governments, the Bill and Melinda Gates Foundation, the Wellcome Trust and the World Economic Forum, has the mission of accelerating the development of vaccines against emerging infectious diseases and making fair access to them possible during outbreaks. It is working with medical authorities around the world and vaccines manufacturers to support the development of COVID-19 vaccines.
In a world characterised by increasing population density, human mobility and climate change, emerging infectious diseases are a real and growing threat for world health safety. Epidemic diseases affect everybody and do not respect frontiers. The costs of emerging infectious diseases are enormous in human as well as in economic terms. Vaccines are one of the most powerful tools in the fight against epidemics. Notwithstanding this, historically the development of vaccines has involved work that is risky, time-consuming and expensive. It is especially challenging to plan for the emergence of infectious diseases, given that there is only limited market potential for vaccines against them —which is not currently the case— and it is difficult to test them. A better system is necessary to accelerate the development of vaccines against emerging infectious diseases. The CEPI has moved quickly and urgently to coordinate with global medical authorities and its members to swiftly develop candidate vaccines against the disease. Its approach includes overcoming critical points between the many organisations involved in research and development, the financing of new and innovative technological platforms which have the potential to quickly accelerate the development and manufacture of vaccines against previously unknown pathogens, and to support and coordinate activities to improve the collective response to epidemics. COVID-19 has led to these concepts being put into practice and tested.
Which technologies are being used in COVID-19 vaccine research?In February the CEPI started studying the range of candidates for a COVID-19 vaccine by used sources of all types, including vaccine candidate products under evaluation and included in the continuously updated WHO list of authorised products. It also studies the information arising from announcements, direct communications with vaccine developers, clinical trial and financial databases, press releases and publically available literature.
On 8 April 2020 they had collected information on 115 candidate vaccine products at different stages of development. 78 of them have been confirmed to be active and this is not the case for 37 other candidates. The projects include a broad range of technological platforms, with traditional or new approaches. The majority are in exploratory or preclinical stages. However, 5 of the candidate products have already entered the clinical development phase:
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mRNA-1273. ARNm vaccine that codifies protein S encapsulated in lipid nanoparticles (Moderna).
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Ad5-nCoV. Type 5 adenovirus vector that expresses protein S (CanSino Biologicals).
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INO-4800. DNA plasmid that codifies protein S administered by electroporation (Inovio Pharmaceutical).
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LV-SMENP-DC. Modified dendritic cells with a lentiviral vector that include minigenes that express conserved structural protein domains and proteases (Shenzhen Geno-Immune Medical Institute).
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Pathogen-specific aAPC. Antigen presenter cells modified with lentiviral vector (Shenzhen Geno-Immune Medical Institute).
It has to be emphasised that, specifically, Moderna started clinical tests of its ARNm-based vaccine only 63 days after the identification of the genetic sequence of the virus.
The most surprising characteristic of all of the COVID-19 vaccines under development is the wide range of technological platforms that are under evaluation. Some of these have not been authorised yet by the regulatory bodies, including the nucleic acid (DNA and RNA) vaccines and the viral vector vaccines (replicants and non-replicants). More specifically, none of the projects which are now in clinical phase uses an authorised platform for the manufacture of preventive vaccines. Nevertheless, experience in fields such as oncology encourages developers to take advantage of the opportunities offered by these next generation, to achieve faster development and greater manufacturing capacity. On the other hand, half of the preclinical phase candidates use conventional technologies (recombinant proteins, attenuated live virus or inactivated virus and virus-like particles [VLP]). Those which use subunits of recombinant proteins stand out in first place, more specifically purified recombinant protein S (obtained by genetic engineering), as complete protein, a fragment or as fusion protein.
For some platforms, adjuvants may improve their immunogenicity and make it possible to use lower doses, thereby enabling more people to be vaccinated. At least 10 developers have shown plans to develop adjuvanted vaccines against COVID-19, and some of the major vaccine developers, such as GlaxoSmithKline, Seqirus and Dynavax, have promised to offer their adjuvants (AS03, MF59 and CpG 1018, respectively) for vaccines developed by others.
Although some major multinational vaccine developers (such as Janssen, Sanofi, Pfizer and GlaxoSmithKline) are involved in developing COVID-19 vaccine, many of the main developers are small and/or have no experience in the large-scale manufacturing of vaccines. It is therefore important to ensure the coordination of vaccine manufacturing and supply capacity, together with sufficient capacity to satisfy demand.
A very long time is normally needed to develop a vaccine, from 5 to 10 years. Is it possible to shorten this period?The need to quickly develop a vaccine against SARS-CoV-2 arose at a time when basic knowledge of the genome and structural biology may give rise to a new era in vaccine development. In the last decade the scientific community and vaccine industry have been asked to respond urgently to epidemics of H1N1 influenza, Ebola, Zika and now SARS-CoV-2. Although monovalent H1N1 influenza vaccine was not available before the pandemic peaked in the northern hemisphere, it was produced quite quickly. This was mainly because influenza vaccine technology was already quite well developed, and the regulatory bodies had already established the procedure for authorising new strains. The pandemic strain was added to the seasonal vaccines. Other cases, such as the SARS and Zika epidemics, finished before their corresponding vaccines had been developed, leaving the manufacturers with financial losses and delaying other vaccine development programs.
The general stages of the vaccine development cycle are:
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The exploratory phase.
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Preclinical phase.
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Clinical development.
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Regulatory revision and approval.
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Manufacturing.
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Quality control.
Clinical development is a three-phase process. During phase I small groups of people are given the test vaccine. Phase II of the clinical study is more expansive and the vaccine is administered to individuals with certain characteristics (such as their age and physical health) which are similar to those of the target group for the new vaccine. In phase III the vaccine is administered to thousands of people, testing its efficacy and safety. Many vaccines are subjected to formal phase IV studies (post-commercialisation), after they have been approved and authorised.
This whole process is both long and costly; the majority of products which commence the preclinical phase are rejected in the following phases, and only a few are commercialised. Due to the cost and high failure rate, developers usually follow a lineal sequence of steps with multiple pauses for data analysis and manufacturing process checks. A new pandemic paradigm is needed for rapid vaccine development, starting quickly and with many of its steps executed simultaneously prior to the confirmation of the success of the previous step, which leads to a high level of financial risk. For example, before testing a vaccine in human beings, it is always necessary to have abundant information from preclinical experimentation in animals. It is now possible to commence trials in phase I in humans while the package of preclinical experimentation is still taking place in animals. This has made it possible to start phase I trials in healthy adults for several candidate products, even though complete preclinical data were not available.
Is it safe to bring forward deadlines?If we take the first vaccine to be subjected to clinical research as an example, and based on experience with vaccines for oncology, it can be said that although the ARNm-based platform is safe in humans, the same is not necessarily true of this COVID-19 vaccine. The National Institute of Allergy and Infectious Diseases (NIAID), which works with Moderna in developing the vaccine, argues that the risk of delaying the progress of vaccines is far higher than the risk of causing disease in healthy volunteers. However, there is no unanimous agreement on this; Shibo Jiang, who has worked developing vaccines and treatments for coronavirus since 2003, states that “we have to urgently develop measure to fight the new coronavirus, but safety is always the first consideration”. He believes that standard protocols are essential to protect health.
A specific concern for this vaccine is the possibility of pulmonary disease exacerbation occurring in any of the vaccinated individuals due to an anomalous immune response. This adverse effect may be associated with the antibody response, which the virus may take advantage of to aid infection, or Th2 lymphocyte-mediated allergic inflammation. Decades previously, the vaccines developed against another coronavirus, infectious feline peritonitis, increased the risk that cats would develop the disease caused by the virus. Similar phenomena have been observed in studies in animals for other viruses, including the coronavirus that causes SARS; in this case worrying immune responses were observed in ferrets and monkeys, but not in mice. Additionally, some viral protein fragments may cause stronger or less risky immune responses than others, and it makes sense to learn this in animal studies before testing them in humans.
Since the 1960s, tests for candidate vaccines against diseases such as dengue fever, respiratory syncytial virus (RSV) and severe acute respiratory syndrome (SARS) have displayed a paradoxical phenomenon: some animals or individuals who had received the vaccine before being exposed to the virus developed more severe disease than did those who had not been vaccinated. There is an urgent need to understand how the immune system reacts not only with the pathogen but also with the vaccine itself, as these data are crucial for the attempt to develop a vaccine that is both safe and effective.
How is it possible that prototype vaccines against SARS-CoV-2 have become available in such a short time?Influenza has given us scientific experience regarding the possibility of unforeseen influenza pandemics appearing. Thanks to this, pharmaceutical companies which develop vaccines have worked intensely and with different vaccine production lines to anticipate these possible situations. The same has occurred with other potentially pandemic viruses. Pharmaceutical companies have worked unceasingly with molecules that are vaccine candidates against these viruses. Vaccine technology too has evolved significantly in candidate molecule selection techniques as well as production culture and synthesis, together with release-administration systems.
The speed with which the genetic sequence of SARS-CoV-2 was discovered and the use of existing new vaccine development lines against other viruses have permitted the rapid appearance of several candidate vaccines against SARS-CoV-2. Previous studies with SARS-CoV-1 and MERS-CoV contributed to knowledge of the infective mechanism of SARS-CoV-2 and the selection of candidate molecules for possible vaccines.
Multiple platforms are under development. Those with the greatest potential for swift development include the DNA and RNA-based platforms, followed by those developing recombinant subunit vaccines. RNA and DNA vaccines can be made quickly because they require neither culture nor fermentation, as they use synthetic processes. The experience of developers and regulators with these personal oncological vaccine platforms may facilitate testing and the prompt availability of vaccines.
What research is being conducted in Spain?The Centro Nacional de Biotecnología (CNB) of the Consejo Superior de Investigaciones Científicas (CSIC) is running two projects. Sonia Zúñiga, of the team headed by Luis Enjuanes and Isabel Sola, is developing a complete virus vaccine. This vaccine may offer a broader response than subunit vaccines. Another CSIC team, headed by the scientist Mariano Esteban, is working on a subunit vaccine and aims to create modified vaccinia virus vectors that contain protein S of the SARS-CoV-2 surface.
In Catalonia, a consortium composed of the IRTA, the IrsiCaixa and the Barcelona Supercomputing Centre and a team from the Grifols pharmaceutical company, headed by Bonaventura Clotet and Oriol Mitjà in the Infectious Diseases Department of Germans Trias Hospital, aim to develop a universal vaccine against all types of coronavirus, based on subunit 1 of protein S of the coronavirus envelope, which they consider to be the most useful target region for vaccine design.