The need for rapid development of a vaccine against SARS-CoV-2 comes at a time of an explosion in basic scientific understanding, including in areas such as genomics and structural biology, that is underpinning a new era in vaccine development. Over the past decade, the scientific community and the vaccine industry have been asked to respond urgently to pandemics of H1N1 influenza, Ebola, Zika, and now SARS-CoV-2. The H1N1 influenza vaccine was developed relatively quickly, in large part because influenza vaccine technology was so well developed and that major regulators had previously decided that vaccines made using egg and cell-based platforms could be licensed under the rules used to alter the strain. Although the monovalent H1N1 vaccine was not available before the epidemic peaked in the northern hemisphere, it was soon available as a stand-alone vaccine and was eventually incorporated into commercially available seasonal influenza vaccines.
The severe acute respiratory syndrome (SARS), Ebola, and Zika vaccines did not follow a similar path. The SARS and Zika epidemics ended before vaccine development was completed, and federal funding agencies reallocated funds that had been committed to developing the vaccine, causing financial losses to manufacturers and disrupting other vaccine development programs.
Development of an Ebola vaccine by Public Health Canada was halted when the 2013-2016 Ebola outbreak began. The US government provided funding to speed up vaccine development, which was eventually passed on to Merck. The company continued its development even after the outbreak ended, and stocks of experimental products were available for use in the recent outbreaks in the Democratic Republic of the Congo. The vaccine received conditional marketing authorization from the European Medicines Agency and approval from the US Food and Drug Administration at the end of 2019 and in several African countries thereafter. Some companies working on Ebola vaccines have received outside support and invested their own money to continue development. Even with successful development and licensing, the possibility that commercial markets will maintain multiple vaccines that may need to manufacture relatively few doses of them appears dim.
Reviews of the H1N1 vaccine trial have emphasized the need for new development and manufacturing platforms that can be easily adapted to new pathogens. Vaccine and biotechnology companies are investing heavily in such approaches, with support from the US government and other funders. The National Institute of Allergy and Infectious Diseases led an initiative to support early development and testing of platforms against “model pathogens” from different viral families.1
Our organization, the Coalition for Epidemic Preparedness Innovation (CEPI), an international non-governmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway and the United Kingdom), supports the development of vaccines against five pathogens The epidemiology is on the priority list of the World Health Organization (WHO). We aim to develop reserves of experimental vaccines for each pathogen after these vaccines have completed Phase 2A trials, and we anticipate that they will undergo clinical trials during future outbreaks. CEPI also supports the development of platform technologies to prepare for “Disease X” – a newly emerging epidemic disease, such as Covid-19. The ideal platform will support development from viral sequencing to clinical trials in as little as 16 weeks, demonstrate consistent elicitation of immune responses across pathogens, and be suitable for large-scale manufacturing with a non-pathogenic platform.
Multiple platforms are under development. Among those with the greatest potential for velocity are platforms based on DNA and RNA, followed by those for development of recombinant subunit vaccines. RNA and DNA vaccines can be made quickly because they do not require cultivation or fermentation, and instead use synthetic processes. The expertise of developers and regulators with these platforms for personalized oncology vaccines can facilitate rapid testing and release. There are no approved RNA vaccines yet, but RNA vaccines have entered clinical trials, and regulators have experience reviewing clinical trial applications and associated vaccine manufacturing.
The use of next-generation sequencing and reverse genetics may reduce the development time of more conventional vaccines during epidemics. The Table It lists the main types of platforms and examples of the types of SARS-CoV-2 vaccines being developed in each. A complete and constantly updated list is available from the World Health Organization.2
Even with new platforms, the development of the SARS-CoV-2 vaccine presents challenges. First, although the viral spike protein is a promising immune factor for protection, optimization of antigen design is critical to ensuring an optimal immune response. Controversy continues about the best approach – eg, targeting only the full-length protein or the receptor-binding domain.
Second, preclinical experience with candidate vaccines for SARS and MERS has raised concerns about lung disease exacerbations, either directly or as a result of antibody-dependent enhancement. This detrimental effect may be associated with a type 2 (Th2) helper T cell response. Hence, testing in an appropriate animal model and strict safety monitoring in clinical trials will be critical. (It’s still too early to identify good animal models; rhesus macaques look just as promising, as do hamsters and ferrets. [unpublished data].) If adjuvants are required to generate an adequate immune response or to spare a dose, those that elicit a Th1 response and show a high neutralizing antibody response are theoretically more likely to be protective and avoid the risks of immune disease. However, data and careful regulatory review will be required. (A summary of the recent conference can be found at https://brightoncollaboration.us/brighton-collaboration-cepi-covid-19-web-conference/.)
Third, although protective associations can be inferred from the SARS and MERS vaccine trial, they have not yet been proven. As with naturally acquired infections, the potential duration of immunity is unknown; Likewise, whether or not single-dose vaccines will confer immunity.
The pandemic model requires multiple activities to be carried out under financial risk to developers and manufacturers and without knowing whether a candidate vaccine is safe and effective, including scaling up manufacturing very early to commercial scale before a clinical proof of concept is established. The identifier indicates the identity.
Vaccine development is a long and expensive process. Attrition is high, and it usually takes several candidates and many years to produce a licensed vaccine.3 Due to the cost and high failure rates, developers typically follow a linear sequence of steps, with multiple pauses for data analysis or manufacturing process checks. Rapid vaccine development requires a new pandemic model (see Graph), with a rapid onset and implementation of several steps in parallel before a successful outcome of another step is confirmed, resulting in higher financial risk. For example, for platforms with experience in humans, phase 1 clinical trials may be able to proceed in parallel with testing in animal models.
Once China announced that the new coronavirus had been identified as the cause of the Wuhan outbreak, CEPI contacted its partners who were developing MERS vaccines or working on new platforms. With the potential for more financial support, they and others began developing the vaccine as soon as the first genetic sequence was published, and development is progressing rapidly. The mRNA-based SARS-CoV-2 candidate entered a phase 1 clinical trial on March 16, less than 10 weeks after the release of the first genetic sequence; A Phase I trial with a non-replicating vector-based vaccine has received regulatory clearance to begin Phase I studies in China. Other phase I trials of the DNA vaccines are expected to begin in April.
For some candidates, additional clinical trial materials are now being manufactured for phase II studies; Moving quickly beyond phase 2 trials means that manufacturing will need to scale up to commercial levels before significant safety and immunogenicity data are available. Building manufacturing capacity can cost hundreds of millions of dollars. Furthermore, for new platform technologies, most of which are unlicensed, large-scale manufacturing has never taken place, so facilities capable of mass-producing a product, transferring technologies, and adapting manufacturing processes must be identified, all without knowing whether a vaccine applicable filter.
It is not certain that these new platforms will be scalable or that the current capacity can produce sufficient quantities of a vaccine quickly enough. It is therefore critical that vaccines are also developed using tried and true methods, even if they take longer to get into clinical trials or result in large numbers of doses.
Conducting clinical trials during a pandemic poses additional challenges. It is difficult to predict where and when outbreaks will occur and to prepare experimental sites to coincide with the vaccine’s readiness for testing. In addition, if there are multiple vaccines ready for testing in the second half of 2020, it will be important not to crowd sites or overburden countries and their ethical and regulatory authorities with multiple trials, as happened with Ebola treatments during the 2013-2016 outbreak.
Furthermore, if mortality is high, the population may not accept randomized controlled trials with placebo groups; Although other approaches that address such concerns may be scientifically feasible, they are usually not quick, and interpretation of the results may be more difficult.4 This problem can sometimes be overcome by comparing results with early versus late vaccination, as in “Ebola ça is enough!” Experience. One possible way forward to test multiple vaccines simultaneously is to design an adaptive trial using a single combined control group, so that more participants receive an active vaccine.5 This approach has advantages but can be logistically and statistically complex, and developers often avoid experiments that might generate head-to-head comparison data.
CEPI, as a relatively new organization, has not established mechanisms and financial tools to support the development of pandemic vaccines and will need to raise additional funds to see SARS-CoV-2 vaccines through development and scaling up of manufacturing processes. Although up to several million doses of vaccine may become available as a byproduct of development, in a pandemic situation, once candidate vaccines have been demonstrated to be safe and effective, doses must be manufactured in large quantities. Although some high-income countries may pay for development and manufacturing costs with their populations in mind, there is no global entity responsible for financing or ordering the manufacture of a vaccine. Discussions are ongoing with global stakeholders about the regulation and financing of large-scale manufacture, procurement and delivery of vaccines.
Finally, epidemics will generate a simultaneous demand for vaccines worldwide. Clinical and serological studies will be needed to confirm which populations remain at highest risk once vaccines are available and can form the basis for establishing a equitable vaccine distribution system globally. Some G7 countries have already called for such a global order, for which planning should begin while vaccine development continues.
Although it is unlikely, if the epidemic appears to be ending suddenly before vaccines are ready, we must continue to develop promising candidates to the point where they can be stocked, prepared for trials, and emergency authorization should be obtained in the event of a recurrence of the outbreak. A global financing system that supports inclusive development, industrialization and large-scale dissemination, ensures equitable allocation, and protects private sector partners from significant financial losses, will be a critical component of preparing for future pandemics.