When was the last time you followed the development of a vaccine? My guess is, NEVER, unless you are in the vaccine development business or a scientist who works on vaccines or an enthusiast. For a layperson, it is not a norm to follow the development of a process that takes 10-15 years of research, development and production. But, thanks to the infodemic and a heightened interest in the general public, the coronavirus vaccine is being followed at every step as it takes. Unprecedented times, unprecedented behaviour!
It is predicted that the vaccine for the coronavirus will be soon in the market. If the experts are to be believed, hopefully in 12-18 months. Fingers crossed! But, is it really possible for scientists and the pharmaceutical industry to cut the vaccine development time by 90-95%?
Many scientists, recently, have begun to refute the projected timeline of coronavirus vaccine development as the fastest vaccine developed so far was for Mumps and that took 4 years from being designed in the laboratory to be brought to the market.
Most of the delay in the vaccine development comes from its clinical trial phases. Since vaccines can generate other immune related diseases, vaccine development is minutely reviewed at every step and scientists need to be extremely careful before taking the vaccines to large scale production. The research for the coronavirus vaccine has circumvented many of these procedures to accelerate the process. There are 110 simultaneous ongoing efforts to produce an effective coronavirus vaccine and India alone is making 8 of them. Also, coronavirus vaccines have opened up the prospects and are being developed with range of technology platforms, including nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant protein, live attenuated virus and inactivated virus approaches. This has required several research labs and vaccine producing companies to cooperate with each other and eventually sketch a plan to launch the vaccine in record time. In this commentary, I will discuss some of the reasons which are helping the vaccine industry to meet this unprecedented deadline.
Coronavirus infection produces both virus-specific antibodies and T-cell responses in most infected patients. These antibodies can create an immunological memory in the infected individuals. Vaccines use such mechanisms to develop long-term antibody responses against the virus. Furthermore, from other coronaviruses like SARS and MERS, we know that these antibodies can persist for at least one to two years following the recovery.
Thus, vaccines for coronavirus assure to induce a more potent immune response.
Lessons from other coronaviruses:
Both SARS-CoV1 (SARS) and SARS-CoV2 (Novel Coronavirus) belong to the family of coronaviruses and are believed to have originated in bats. They are closely related RNA viruses, more like cousins who have 80% similarity in their genomes. This is a considerably great overlap for virus genomes because they mutate very frequently and rapidly, which causes a lot of errors in their genomes and create major differences. These genomic similarities make these two viruses so similar that they have similar exterior proteins and use the same proteins to interact with human cell surfaces to enter the cell.
Though the vaccine development of SARS was stalled due to the development of immune diseases during the animal testing caused by the administered vaccine, the sudden disappearance of the virus was the major cause of subjugation of the process. However, the similarity in genomes of SARS and coronavirus and the intensive vaccination studies for SARS has given a major head start for the vaccine development of coronavirus.
Many of the vaccines being developed for coronavirus are quite different, and many use only small portions of the virus, or the virus RNA. This may circumvent the problems with SARS vaccines that used more of the virus. Vaccine development has a large experimental component; we just have to make educated guesses and try different things and see what works. Hence, many different avenues for vaccines are being tested by different labs around the world.
Experience with SARS vaccine development indicates the potential for immune enhancement effects of different antigens, which is a topic of debate and could be relevant to vaccine advancement.
In comparison with other viruses:
Coronavirus is a less deadly virus as unlike HIV, it does not embed its genome into the human genome to make fresh copies of itself. At the same time, due to the presence of a correcting factor in its genetic material polymerisation system, coronavirus also mutates slower than the influenza virus, the dengue virus or HIV.
Though while developing the vaccine scientists need to be updated with the latest mutant of coronavirus, the slow mutation rate of the virus makes it easier for the scientists to keep up with it.
New forms of vaccines:
All over the world, simultaneous research going on for more than 110 vaccines and scientists, this time, are leaving no stones unturned to produce the vaccine for coronavirus. Eight of them are already being tried on humans in control trials. In these 100+ vaccines, some are relying on the traditional methods of dead or weakened viruses to make the vaccine and some are using novel agents like adenovirus or virus nucleic acid to generate immune response. Many of these technologies do not form the basis of any of the licensed vaccines in the market, but extensive usage in fields such as oncology has encouraged next-generation approaches that offer increased speed of development and manufacture. It is also speculated that some of these vaccine platforms may be better suited to more vulnerable sections of demography (such as the elderly, children, pregnant women or immunocompromised patients).
Each of these platforms come with their own strengths. Nucleic acid based novel platforms are also flexible in terms of antigen manipulation and speed of development. This is evident the speed at which Moderna was able to take its mRNA-based vaccine to clinical trial in a short span of 2 months after sequence identification. mRNA based vaccines also give an edge from the traditional manufacturers as they can be scaled up quickly. Since the RNA uses the human body as its bioreactor, the company doesn’t have to manufacture the proteins which normally takes longer time. Viral vectors based vaccines can produce high levels of protein expression and long-term stability, and can also induce strong immune responses. Finally, the already licensed platforms of vaccines based on recombinant proteins can take advantage of existing large-scale production capacity.
For some platforms, adjuvants can also be used to enhance immunogenicity which makes lower doses viable and enables vaccination of more people without compromising protection. So far, at least 10 developers have indicated plans to develop adjuvanted vaccines against COVID-19, and vaccine developers including GlaxoSmithKline, Seqirus and Dynavax have committed to making licensed adjuvants available for use with novel COVID-19 vaccines developed by others.
Thus, using various methods simultaneously to develop this vaccine has increased the chance of having the vaccine sooner than before.
Vaccines, normally, take 10-15 years to develop, and their development typically requires three phases of clinical trials. In Phase 1, the trial vaccine is tested on small groups of people. Upon success of the trial vaccine, during Phase 2, the clinical study is expanded and is given to a specific demography based on age and physical health similar to those who are most affected by the concerned disease. In Phase 3, the vaccine is given to a larger population (usually, several thousand people) and tested for efficacy and safety. The efficacy of the vaccine is determined by comparing the infection rate in the group that received the vaccine dose with the one which received a placebo. Typically, Phase 1 lasts for 1-2 years, Phase 2 lasts for 2-3 years and Phase 3 lasts for 2-4 years. Upon the success of Phase 3, the vaccine development is reviewed and then goes into the scale-up phase where biotech industries increase the production of the vaccine to be launched in the market.
The novel coronavirus's fast spread and impacts on global health and economy have forced scientists to accelerate the development process by skipping or combining various phases of research and has prompted scientists to take unthinkable shortcuts. The approach is underlined with risks but could help in making a vaccine in record time.
Normally, laboratories test vaccines on animals before entering the clinical trial phase. This step could take weeks to months and is not a legally required step. Many biotech laboratories like Moderna have skipped this step to save time and have moved directly into the first clinical trial phase and started their tests on human volunteers. At the same time, Moderna’s phase 1 trial, introduced at-risk populations of older adults (ages 56 to 70) and elderly adults (age 71 and above) to the trial; usually, such populations would be introduced in later phases.
Another approach that is being debated is the human challenge trial. This approach saves time but has major risk involved with it. It is a modified Phase 3 approach where instead of administering the vaccine to a large population and waiting for them to be exposed to the infection, a smaller set of population (usually in 100s of people) is chosen which is intentionally exposed to the infection. This is a more controlled system and may be more effective for diseases like Covid-19 which have a high number of asymptomatic patients. As of June 2nd, a global initiative called 1DaySooner had registered 26,716 people in 102 countries who had signed up for such trials. Similarly, in the anticipation of saving time, Inselspital, the University Hospital of Bern, has declared that after testing the prospective vaccine in a smaller group to ensure it is not toxic, they plan to immunize a larger Swiss population in the next six months and then produce for a world market.
The hastened coronavirus vaccine development programs are being strongly supported by the governments all over the world by multifold increase in the funds for vaccine development.
While the funding for the Vaccines for Children entitlement program stood at $1 billion in 2002, the U.S. Biomedical Advanced Research and Development Authority (BARDA) has given $1.2 billion to AstraZeneca, which has agreed to supply at least 400 million doses of the Oxford University vaccine. Furthermore, the Bill & Melinda Gates Foundation has announced a commitment of $125 million to develop and distribute COVID-19 diagnostics, therapies, and vaccines. Of this, $50 million is a new funding to Gavi, the Vaccine Alliance, to support its future efforts to deliver COVID-19 vaccines to lower-income countries.
Similarly, the European Commission has registered €7.4 billion, equivalent to $8 billion, in pledges from donors worldwide during the Coronavirus Global Response pledging event. The pledge will fund into the collaborative development and universal deployment of diagnostics, treatments and vaccines against coronavirus.
At the same time, Indian government has allocated Rs 100 crores from the PM-CARES (Prime Minister’s Citizen Assistance and Relief in Emergency Situations) Fund for developing a vaccine against coronavirus disease (Covid-19). And, according to the Department of Biotechnology, already, there are as many as 25 vaccine development initiatives underway in India. Additionally, Serum Institute of India has dedicated Rs 300 million to Rs 400 million for making around 3-5 million doses of coronavirus vaccine per month and has also agreed to invest roughly Rs 6 billion on making a new manufacturing unit to solely produce coronavirus vaccines.
Simultaneous production and clinical trials:
The entire approach of coronavirus vaccine designing and development is very unique. Normally, companies would wait for the vaccines to get deeper into their clinical trials to gain more assurance on the high efficiency of the product before investing in their manufacturing scale-up. Such waits usually take months and in case of coronavirus vaccine researchers don’t have that time to spare. Planning later phases before the earlier phase data is analyzed is a business risk, but it’s a risk that most of the production companies are ready to take given the scale of the pandemic. In that perspective, many vaccine developers have contracted production facilities from different countries which are working on the vaccine production in concurrence with the clinical trials. For example, the Oxford University vaccine, ChAdOx1 has at least seven manufacturing sites around the world. Those include Serum Institute of India (SII), Astra Zeneca and several sites in Europe and China. SII has declared to begin the production in June 2020 in concurrence with the vaccine clinical trials and both SII and Astra Zeneca aim to launch 5-6 million doses of the vaccine by September 2020. Having manufacturing units set up in several countries reduces transportation time considerably. Similarly, Moderna has also already begun manufacturing the material for phase 2 trials to save time. Some companies like Sinovac have already prepared and packaged thousands of shots of the vaccine, which is still in the human trial phase. The company aims to make 100 million doses per year to combat the virus. In a different approach, Pfizer and BioNTech are collaborating on four vaccine candidates simultaneously to identify the most promising program which at the clinical-stage will be expanded by BioNTech in Germany and Pfizer in the USA and Belgium. Similarly, Bill and Melinda Gates Foundation has taken an organization that was focused on HIV and malaria and polio eradication, and almost entirely shifted it to work on tackling coronavirus.
Also, clinical trials require large resources to organise testing on tens of thousands of people. To manage such large scale testing plans in a short time, both small companies like Moderna and big pharma like Pfizer are hiring extra manpower to be able to increase manufacturing production.
Since there are several approaches in testing there is a higher probability of success, and pharmaceutical companies have been engaged early, scaling up production and working out logistics for distribution even before there is evidence the vaccine will work will certainly save an ample amount of time.
Vaccine distribution is the next big problem that has to be dealt with. GAVI, the vaccine alliance supported by Bill and Melinda Foundation is working with distribution companies such as UPS to come up with high technology solutions, and are also looking into drone technology to deliver equipment.
Thus, breaking the traditional rules of drug and vaccine development in the face of a virus that has infected 4.5 million people, killed more than 380,000 and devastated the global economy may help us achieve the goal of identifying, testing, producing and distributing the vaccine in a record time of just 12 to 18 months. And in this greatest mix of collaborative and competitive race against the time, even if 6% of vaccine candidates (which is the normal percentage of vaccines) end up making it to market, the good news is that we would have at least 6 effective vaccines against coronavirus.