When ready, a coronavirus vaccine must reach all
More than 115 vaccines are under development to bring the novel coronavirus pandemic to a halt. It is time to spruce up a global supply mechanism to ensure everyone gets the vaccine, say Arun Kumar* and Tung Thanh Le*.
doi:10.1038/nindia.2020.81 Published online 1 May 2020
Mankind has its hope pinned on the fast development and mass production of a new vaccine as the most important research and development effort in containing the rapid global spread of the novel coronavirus pandemic. The severity of the public health crisis, set off by the virus SARS-CoV-2 (Severe acute respiratory syndrome-Coronavirus-2) first reported in Wuhan, China in December 2019, has triggered more than 115 vaccine projects around the world.
After a similar epidemic – the Ebola outbreak of 2014 in West Africa – international research bodies and governments felt the need to join forces in the search for new vaccines. This formed the basis of The Coalition for Epidemic Preparedness Innovations (CEPI) set up by the Governments of India and Norway, the Bill and Melinda Gates Foundation, the Wellcome Trust and the World Economic Forum.
Some of the projects in India by Bharat Biotech, Biological E, Indian Immunologicals, Mynavax, Serum Institute and Zydus Cadila are part of such global efforts to develop vaccine candidates. CEPI is facilitating the development of nine COVID-19 vaccines – including those by Moderna, CureVac, Inovio, University of Oxford, Insitut Pasteur/Themis Biosciences, Novavax, University of Hongkong, University of Queensland and Clover Biopharmaceuticals, across six traditional and novel platform technologies. As of April 2020, three of these vaccine candidates had started phase I clinical trials.
Vaccine development is a lengthy process and involves various stages including exploratory and preclinical research, clinical development, regulatory review, and manufacturing. Each of these steps can take several years. Some novel platform technologies and approaches are proving to reduce these long timelines. Such platform technologies could provide a universal framework for vaccine design, manufacturing and analytical protocols for known and unknown pathogens. When these standardized and validated processes are applied across multiple vaccine targets, they could help in accelerating animal and clinical testing, engagement of critical partners and licensure processes across jurisdictions. Additionally, implementation of several steps in parallel, before confirming the successful outcome of previous steps, could also accelerate the vaccine development process.
Types of vaccines
Vaccines based on genetic instructions (as DNA or RNA) offer advantages over traditional approaches because of speed, ease in antigen design and the generic process of manufacturing. These vaccines avoid the use of cell culture, are fully synthetic, and are directly delivered into the cells where protein synthesis takes place.
Messenger RNA (mRNA) vaccines (consisting of RNA strands coding antigenic part of the pathogen) are very attractive because of the short-half life and direct delivery of antigen-encoded sequence into the cytoplasm. A chemically modified mRNA vaccine (mRNA-1273) against SARS-CoV-2 has been developed by Moderna and has started phase I trial. The previous Phase I trial based on this technology induced robust immune responses. Demonstrating the speed of this platform, just after sequence identification, Moderna started the vaccine development process and within 63 days initiated a Phase I trial.
Another mRNA based COVID-19 vaccine candidate in pre-clinical stages is being developed by CureVac, a company based in Tubingen, Germany. CureVac’s technology uses naturally occurring nucleotides and recently has shown that 1 ug formulation of its Rabies mRNA vaccine can induce strong immune response in humans. Additionally, CureVac is in the process of developing a fully automated proprietary mobile manufacturing platform, RNA PrinterÒ, which may further enhance speed and help with rapid responses to outbreak globally. Very recently, BioNTech in partnership with Pfizer started Phase I/II clinical trial for a COVID-19 vaccine, BNT162. Other advanced vaccine development candidate based on RNA technology, including Imperial College London, Tongji University/Chinese Centre for Disease Control and Prevention and Translate Bio/Sanofi, are also progressing with impressive speed.
Inovio’s DNA vaccine (INO-4800) against COVID-19, initiated phase 1 trials within 86 days. Scientists at Inovio started to design and synthesis of DNA vaccine, which consists of a DNA plasmid containing genes encoding for the SARS-CoV-2 spike protein. This vaccine can be given through the skin and with the help of an innovative next-generation electroporation device. This delivery device allows smooth entry of DNA into the human cells with the help of an electric current. In previous preclinical and clinical studies, Inovio’s platform technology induced robust T-cell and antibody responses. Zydus Cadila recently has been recommended for funding support from India’s Department of Biotechnology (DBT) for advancing its DNA-based Covid-19 vaccine.
Viral-vectors are being exploited for gene delivery and vaccines based on this approach offer a high level of protein expression, extended stability and provoke strong humoral (antibody mediated) and cellular (T-cell mediated) immune responses. Antigens of interest can be expressed efficiently. China’s CanSino Biologics with its recombinant COVID-19 vaccine based on Adenovirus Type-5 vector (Ad5), has moved into the Phase II trial. The University of Oxford started the development of a COVID-19 vaccine based on a replication deficient ChAdOx1 platform (chimpanzee adenovirus vector) and began Phase I/II clinical trial on 23 April 2020. The Serum Institute of India partnered with the University of Oxford and stated to start production of vaccine in next 2-3 weeks.
Additionally, AstraZeneca also team up with Oxford for mass production of the COVID-19 vaccine. Several clinical trials have proved that it induces immunity and is safe to use against a range of pathogens. Another CEPI funded consortium led by the Institute of Pasteur, Themis Biosciences and University of Pittsburgh is developing a COVID-19 vaccine based on Measles vector (MV). The low cost of manufacturing and production of large quantities in less time makes viral vectored vaccines favourable for use in low-income and middle-income settings.
Recombinant nanoparticles are non-infectious particles and mimic conformational and structural properties of the native virus but lack genetic material. These properties make them a potential platform technology for vaccine development. Novavax developed a COVID-19 vaccine (NVX-CoV2373) based on proprietary recombinant nanoparticle technology. The NVX-CoV2373 vaccine is designed to make a stable form of prefusion form of spike protein. Immunisation of NVX-CoV2373 in animals showed strong immunogenicity. Novavax is expecting to start phase I clinical trial in mid-May (within 125 days after sequence identification).
This platform has the potential to rapidly generate and manufacture vaccine candidates within 90 days (from the identification of gene sequence), as seen in an influenza A/Anhui/1/2013 (H7N9) and Ebola vaccine candidates. Medicago is another advance VLP candidate with ready material for pre-clinical studies.
Traditional methods such as inactivated and live attenuated approaches are among the most advance candidates. Recently, an inactivated vaccine developed by Sinovac announced commencement of phase I trial, meanwhile, Wuhan institute of Biological Product’s vaccine entered in to the phase II trial. Indian vaccine developer Bharat Biotech along with the University of Wisconsin has started development of a COVID-19 vaccine based on self-limiting version of influenza virus, CoroFlu. Scientists at the University of Hong Kong (HKU) developed a novel rapid response technology based on live attenuated influenza vaccine platform, DelNS1 LAIV.
The non-structural protein 1 (NS1) element, which makes flu virus strongly immunogenic and less virulent, was deleted in DelNS1 LAIV. Their COVID-19 vaccine candidate was developed by incorporating Receptor Binding Domain (RBD) of SARS-CoV-2 into DelNS1 LAIV on its surface. Use of only RBD domain may avoid induction of antibody dependent enhancement of disease. This vaccine could prevent both SARS-CoV-2 and influenza infections and can be administered by nasal route. A phase I trial is expected to start in the beginning of July this year.
The University of Queensland (UQ) – one of the first runners of the recombinant protein approach – has developed molecular clamp technology that keeps the spike protein of SARS-CoV-2 in stable form, which allows the immune system to be able to recognize it. Influenza, Nipah, and MERS coronavirus are some of the vaccine candidates that are currently under development based on this rapid response platform technology. Scientists at UQ were able to generate the COVID-19 vaccine candidate within 21 days after publication of SARS-CoV-2 sequence. CEPI just announced a partnership with the Clover Pharmaceuticals for development of a SARS-CoV-2 spike (S)-protein subunit vaccine candidate based on innovative Trimer-Tag© technology. Efforts of Vaxine, SK Bioscience and G+Flas Life Science are also encouraging and advancing development of COVID-19 vaccines based on the recombinant approach.
When combined with recombinant protein-based vaccines, adjuvants (substances that modulate and enhance immune response when combined with antigen) can help in boosting stronger and long-lasting immunity. Furthermore, adjuvants also increase dose-sparing capacity without affecting protection potential and allow more vaccine doses to be made available, which is especially important in a pandemic situation. GlaxoSmithKline, Seqirus and Dynavax have committed to making innovative licenced adjuvants (ASo3, MF59 and CpG 1018), respectively) available to partners supported by CEPI to enhance the development of effective vaccines against SARS-CoV-2.
Vaccine for all
Both novel and traditional approaches to COVID-19 vaccine development offer different value propositions in relation to speed of development and scale of manufacture over short and long terms. CEPI has a diverse portfolio of candidates based on a wide range of vaccine technologies — including novel platform technologies and other more established approaches — to maximise its chances of success.
When a safe and effective vaccine against COVID-19 is licenced for use, there will be simultaneous demand around the world. Currently, there is no global entity responsible for financing or ordering such a vaccine manufacture, nor is there a globally fair allocation system for any vaccines produced. It will be vital that such a system is in place to ensure that everyone who needs it gets the vaccine, and that no one is left behind. In response, the WHO and global leaders from around the world launched the Access to COVID-19 Tool (ACT) accelerator, of which CEPI is a founding member, to speed up development, production and access to vaccines and therapeutics.
Globally fair allocation of vaccines is a challenge that must be urgently and collectively addressed by governments, global health leaders, and regulators while the race for a COVID-19 vaccine picks up pace.
[*The authors are from the Coalition for Epidemic Preparedness Innovations (CEPI), Oslo, Norway.]
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