Vaccines take over a decade to develop in a safe and effective manner. Vaccine candidates must first be proved to work in the lab and then tested for toxicity in animals before reaching early phase clinical trials.
Once they have reached human trials, a vaccine must be tested for safety (phase I) and side effects (phase II) before entering large scale clinical trials (phase III). There is a high level of attrition as vaccines pass through the various stages of clinical trials, either because they are unsafe, ineffective or both. It is difficult to fast-track vaccine development; these stages cannot be skipped.
The covid-19 pandemic is accelerating the slow process of vaccine development but how long will it be until we can effectively vaccinate populations? This article looks at how the industry is responding to the covid-19 outbreak in the race for a vaccine.
According to the World Health Organisation (WHO), there are more than 40 vaccines against SARS-CoV-2 in development, with two already at the clinical trial stage. The Coalition for Epidemic Preparedness Innovations (CEPI), a foundation that takes donations to finance independent research projects to develop vaccines against emerging infectious diseases, is currently working with eight companies, all of which are having to adapt to accelerate their vaccine development process.
The first stage of vaccine development is research-intensive and involves the identification of natural or synthetic antigens that might help combat the disease. However, within a week of sequencing the SARS-CoV-2 genome, Chinese scientists had shared it publicly. Sharing the viral genome globally has allowed for an acceleration of the early development stage. Researchers at Imperial College, for example, took just two weeks from receiving the genome to producing a candidate vaccine.
Another way of accelerating the development process is to run trials in parallel. Researchers at Oxford University are currently recruiting for a safety trial in humans for a vaccine candidate that uses a chimpanzee adenoviral vector. Provided these go smoothly, they will move to larger trials to assess efficacy. The same vaccine will undergo animal trials concurrently. This is unusual as animal work should normally be completed before human trials can begin. However, the chimpanzee adenoviral vector has been studied extensively and used safely in thousands of subjects in vaccines targeting over ten different disease types. This makes it easier to justify the accelerated move to human testing. Regulatory approval can also be accelerated if similar products have been approved before.
For similar reasons, many companies are also repurposing vaccines. Coronaviruses have caused two recent epidemics: SARS and MERS. In both cases, work started on vaccines was subsequently stopped when the epidemics were successfully contained. Inovio Pharmaceuticals had already started to work on a DNA vaccine for MERS prior to the covid-19 outbreak, allowing the company to quickly develop a potential vaccine for covid-19. Sanofi is repurposing a SARS protein vaccine and Novavax are working on several repurposed vaccines that will reportedly be ready for human trials in the spring.
As well as the more traditional techniques being used, such as live-attenuated and recombinant vaccines, new techniques are being used to develop a vaccine against SARS-CoV-2: RNA vaccines. These are faster and cheaper to develop than the more traditional vaccines as researchers don't need to grow large amounts of the virus in the lab, which overcomes both regulatory and manufacturing hurdles. However, no RNA vaccine has ever been approved for use and the safety of such vaccines is unknown at present. Moderna gave the first dose of their novel RNA vaccine to a human participant on 16 March and currently has 45 participants enrolled in in clinical trials. However, they expect the trials to continue into next year. Although the vaccine may have been quicker to develop, they cannot circumvent the necessary steps to show the vaccine is safe and effective.
One step that can potentially be fast-tracked is authorisation. The European Medicines Agency (EMA) has regulatory mechanisms in place to speed up development and approval. The PRIME scheme was launched to provide early and enhanced scientific and regulatory support to medicines that have the potential to address unmet medical needs. Developers of medicines and vaccines benefitting from PRIME will be eligible for accelerated assessment, reducing the timeframe for the EMA to review applications for market authorisation. The EMA can also grant a conditional marketing authorisation for vaccines where the benefits of immediate availability outweigh the risks of less comprehensive data than normally required. Developers working on vaccines that could be used for the prevention of covid-19 are encouraged to contact the EMA and discuss their research as soon as possible.
Once a safe and effective vaccine has been developed, there are further hurdles such as large-scale manufacturing. Many organisations researching a vaccine don't have the required manufacturing capacity. Vaccine development is high risk, with many candidates failing to reach clinical application. Further, manufacturing facilities tend to be tailored to specific vaccines. Scaling these facilities up when the future deployment of a vaccine is still in the uncertain early stages is not commercially viable. However, CEPI can shoulder some of that risk by providing funding not only to research facilities developing vaccine candidates but also to manufacturing facilities in parallel. At the same time as clinical trials are taking place in Oxford, production of the vaccine is being scaled up ready for larger trials and possible future deployment. By starting the scale up at an early stage, researchers are ensuring that sufficient doses will be available as soon as possible if the trials prove that the vaccine is safe and effective.
Researchers in Beijing studied the viral genome from 103 infected patients and identified two types of the virus, S and L. At present, scientists do not know how the underlying genetic differences in the two strains relate to disease severity. Genetic analysis of a man in the US who tested positive in January has shown that it is possible to be infected by both strains. Any vaccine candidate will have to target features present in both strains in order to be effective. The genetic differences between the two strains are small at present and unlikely to affect the production of proteins, so as not to change the way the virus works. Genetic diversity doesn't necessarily mean the virus is changing however we can expect more strains to emerge. It is generally agreed that, once infected, individuals are unlikely to be infected again, unless the virus mutates to overcome host immunity. It is possible that this selection pressure will lead to an outbreak of a new strain, in a similar fashion to seasonal flu. As is the case with flu, new variants can emerge that infect individuals, whether or not they have been infected in the past. This will clearly have an impact on the long-term efficacy of vaccines currently in development.
Special thanks to Emily Lockey, trainee solicitor, for drafting this article
We are all navigating uncharted waters as business and society faces up to the impact of COVID-19. We very much hope you and your loved ones remain in good health.
Please be assured that Fieldfisher is continuing to work with clients to navigate COVID-19 related issues and on business as usual needs. Do get in touch with us if you would like to chat anything through.
The covid-19 pandemic is accelerating the slow process of vaccine development but how long will it be until we can effectively vaccinate populations? This article looks at how the industry is responding to the covid-19 outbreak in the race for a vaccine.
Current vaccine candidates
According to the World Health Organisation (WHO), there are more than 40 vaccines against SARS-CoV-2 in development, with two already at the clinical trial stage. The Coalition for Epidemic Preparedness Innovations (CEPI), a foundation that takes donations to finance independent research projects to develop vaccines against emerging infectious diseases, is currently working with eight companies, all of which are having to adapt to accelerate their vaccine development process. The first stage of vaccine development is research-intensive and involves the identification of natural or synthetic antigens that might help combat the disease. However, within a week of sequencing the SARS-CoV-2 genome, Chinese scientists had shared it publicly. Sharing the viral genome globally has allowed for an acceleration of the early development stage. Researchers at Imperial College, for example, took just two weeks from receiving the genome to producing a candidate vaccine.
Another way of accelerating the development process is to run trials in parallel. Researchers at Oxford University are currently recruiting for a safety trial in humans for a vaccine candidate that uses a chimpanzee adenoviral vector. Provided these go smoothly, they will move to larger trials to assess efficacy. The same vaccine will undergo animal trials concurrently. This is unusual as animal work should normally be completed before human trials can begin. However, the chimpanzee adenoviral vector has been studied extensively and used safely in thousands of subjects in vaccines targeting over ten different disease types. This makes it easier to justify the accelerated move to human testing. Regulatory approval can also be accelerated if similar products have been approved before.
For similar reasons, many companies are also repurposing vaccines. Coronaviruses have caused two recent epidemics: SARS and MERS. In both cases, work started on vaccines was subsequently stopped when the epidemics were successfully contained. Inovio Pharmaceuticals had already started to work on a DNA vaccine for MERS prior to the covid-19 outbreak, allowing the company to quickly develop a potential vaccine for covid-19. Sanofi is repurposing a SARS protein vaccine and Novavax are working on several repurposed vaccines that will reportedly be ready for human trials in the spring.
As well as the more traditional techniques being used, such as live-attenuated and recombinant vaccines, new techniques are being used to develop a vaccine against SARS-CoV-2: RNA vaccines. These are faster and cheaper to develop than the more traditional vaccines as researchers don't need to grow large amounts of the virus in the lab, which overcomes both regulatory and manufacturing hurdles. However, no RNA vaccine has ever been approved for use and the safety of such vaccines is unknown at present. Moderna gave the first dose of their novel RNA vaccine to a human participant on 16 March and currently has 45 participants enrolled in in clinical trials. However, they expect the trials to continue into next year. Although the vaccine may have been quicker to develop, they cannot circumvent the necessary steps to show the vaccine is safe and effective.
One step that can potentially be fast-tracked is authorisation. The European Medicines Agency (EMA) has regulatory mechanisms in place to speed up development and approval. The PRIME scheme was launched to provide early and enhanced scientific and regulatory support to medicines that have the potential to address unmet medical needs. Developers of medicines and vaccines benefitting from PRIME will be eligible for accelerated assessment, reducing the timeframe for the EMA to review applications for market authorisation. The EMA can also grant a conditional marketing authorisation for vaccines where the benefits of immediate availability outweigh the risks of less comprehensive data than normally required. Developers working on vaccines that could be used for the prevention of covid-19 are encouraged to contact the EMA and discuss their research as soon as possible.
Once a safe and effective vaccine has been developed, there are further hurdles such as large-scale manufacturing. Many organisations researching a vaccine don't have the required manufacturing capacity. Vaccine development is high risk, with many candidates failing to reach clinical application. Further, manufacturing facilities tend to be tailored to specific vaccines. Scaling these facilities up when the future deployment of a vaccine is still in the uncertain early stages is not commercially viable. However, CEPI can shoulder some of that risk by providing funding not only to research facilities developing vaccine candidates but also to manufacturing facilities in parallel. At the same time as clinical trials are taking place in Oxford, production of the vaccine is being scaled up ready for larger trials and possible future deployment. By starting the scale up at an early stage, researchers are ensuring that sufficient doses will be available as soon as possible if the trials prove that the vaccine is safe and effective.
Current issues
Researchers in Beijing studied the viral genome from 103 infected patients and identified two types of the virus, S and L. At present, scientists do not know how the underlying genetic differences in the two strains relate to disease severity. Genetic analysis of a man in the US who tested positive in January has shown that it is possible to be infected by both strains. Any vaccine candidate will have to target features present in both strains in order to be effective. The genetic differences between the two strains are small at present and unlikely to affect the production of proteins, so as not to change the way the virus works. Genetic diversity doesn't necessarily mean the virus is changing however we can expect more strains to emerge. It is generally agreed that, once infected, individuals are unlikely to be infected again, unless the virus mutates to overcome host immunity. It is possible that this selection pressure will lead to an outbreak of a new strain, in a similar fashion to seasonal flu. As is the case with flu, new variants can emerge that infect individuals, whether or not they have been infected in the past. This will clearly have an impact on the long-term efficacy of vaccines currently in development.
Special thanks to Emily Lockey, trainee solicitor, for drafting this article
We are all navigating uncharted waters as business and society faces up to the impact of COVID-19. We very much hope you and your loved ones remain in good health.
Please be assured that Fieldfisher is continuing to work with clients to navigate COVID-19 related issues and on business as usual needs. Do get in touch with us if you would like to chat anything through.