Why does it take years to develop a new coronavirus vaccine?



Vaccine development for the novel coronavirus infection (COVID-19) will take at least 12-18 months, said Anthony Forsy, director of the National Institute of Allergy and Infectious Diseases, and WHO Secretary-General Tedros Adamanom. Researchers have published reports on why vaccine development takes years, the current status and challenges of vaccines in development, and the development timeline. When you read the contents, it is a tremendous content that you can realize that '18 months is not enough'.

SARS-CoV-2 Vaccines: Status Report: Immunity

https://www.cell.com/immunity/fulltext/S1074-7613(20)30120-5

The novel coronavirus (SARS-CoV-2) is a member of the coronavirus group that causes diseases in mammals and birds. Although multiple types of coronavirus have been confirmed, it is the alpha coronavirus called 'HCoV-229E' 'HCoV-NL63' and the beta coronas 'HCoV-OC43' 'HCoV-HKU1' that cause human diseases. It's a virus. 'SARS-CoV-1' called SARS and 'MERS-CoV' called Middle East respiratory syndrome coronavirus belong to beta coronavirus like SARS-CoV-2.

SARS-CoV-2 is covered with a spike protein (S protein) that is a glycoprotein, which binds to angiotensin-converting enzyme II (ACE2) on human cells to invade and infect human cells. Is believed to be.

◆Current status of therapeutic drug development



As of April 2020, clinical trials of

remedecivir and other SARS-CoV-2 therapeutic agents are being conducted in the United States and China. Remdecivir was promoted to treat the Ebola virus epidemic, and since it has already been proven safe, it is expected to accelerate the process of clinical trials. Clinical trials have also begun on the combination of the HIV inhibitors lopinavir and ritonavir . In addition, the results of various clinical trials such as a drug that recombines human ACE2 to neutralize the virus and prevent lung damage, influenza drug Arbidol, serum therapy, a method using immunoglobulin G obtained from cows, etc. Will be announced in the coming weeks and months.

◆ Summary of what we know about vaccine development
Vaccine technology has improved dramatically over the last decade thanks to scientific research. As a result, SARS-CoV-2 was quickly identified and the genomic sequence published by Chinese researchers was shared with researchers around the world. In addition, because the SARS-CoV-1 and MERS-CoV vaccines targeted the S protein, and that SARS-CoV-1 and SARS-CoV-2 act on the same ACE2, researchers have targeted vaccines. I was able to understand quickly.

Some of the SARS-CoV-1 vaccines developed so far have been tested in animals, and many were able to protect the animals from SARS-CoV-1, but on the other hand, immunological bactericidal functions were recognized. I couldn't do it. Also, in the mouse experiment, lung damage and inflammation due to eosinophils occurred, and in the experiment targeting the ferret, liver damage was caused. However, overall, vaccinated animals had a higher survival rate and were able to lower virus titers compared to non-vaccinated animals. It is necessary to confirm that the vaccine that has been shown to be effective in animal experiments is safe for humans, as is the case with SARS-CoV-2.



However, there are concerns about how long the immunity will last. Regarding the news that ``I tested a COVID-19 patient after recovery and turned positive again'', it is likely that it was a false negative, but it is possible that it will be infected again several months to several years after the immunization. There is a nature. An effective SARS-CoV-2 vaccine needs to overcome this problem and protect people even when the virus becomes endemic with seasonal epidemics.

And people over the age of 50 need to protect the elderly as SARS-CoV-2 tends to be more severe. However, older people are less responsive to vaccination due to aging. For this reason, it is considered that young people can be vaccinated to stop the spread of the virus and prevent the infection of the elderly.

◆ What are the issues that lie in vaccine development?
The development of a vaccine for human consumption can take years if technology is used that is not yet widely recognized as safe and has not been scaled up for mass production. There is no vaccine for coronavirus on the market and no large-scale manufacturing capability. Many companies and institutions do not have an established pipeline for conducting late-stage clinical trials that allows regulatory approval, and can produce the amount of drug needed to conduct clinical trials. I can't.

There are multiple types of SARS-CoV-2 vaccines, but they all have both advantages and disadvantages as follows.

platform target Presence or absence of human vaccine using the same platform merit Demerit
RNA vaccine S protein None Vaccines are immunogenic and do not have to deal with infectious viruses and can be manufactured quickly. Reactogenicity has been reported and there are safety issues.
DNA vaccine S protein None Easy to scale up without having to deal with infectious vaccines. It has low manufacturing costs, is stable to heat, and has been tested in patients with SARS-CoV-1. Rapid production is possible. Vaccination with a special device is necessary to bring about immunogenicity.
Recombinant protein vaccine S protein Yes against influenza, hepatitis B virus, human papillomavirus There is no need to handle infectious viruses, and it is possible to use adjuvants that enhance immunogenicity. Worldwide manufacturing capacity is limited. It is necessary to confirm that the antigen or

epitope
is complete. High yield is required.
Virus vector vaccine S protein There is against vesicular stomatitis virus ( brand name: Ervebo ) There is no need to deal with contagious viruses and excellent preclinical and clinical data have been demonstrated for many emerging viruses including MERS-CoV. Immunity to viral vectors can negatively impact the efficacy of the vaccine.
Live attenuated vaccine All virions Yes A clear process has been established with several already approved vaccines. Existing infrastructure can be used. Due to the large genome size, it takes time to clone a species of attenuated coronavirus vaccine. Safety tests are needed to scale up.
Inactivated vaccine All virions Yes A clear process has been established with several already approved vaccines. Existing infrastructure can be used, SARS-CoV-1 patients are being tested untouched, and adjuvants that can enhance immunogenicity can be used. You need to handle large numbers of infectious viruses (although you can use attenuated viruses to mitigate them). It is necessary to confirm whether the antigen or epitope is complete.


◆Why does it take so long? The timeline until commercialization looks something like this
As mentioned above, no human coronavirus vaccine has been approved yet. For this reason, many technologies need to be thoroughly tested for safety. After the S protein that is the target of the vaccine has been identified and candidates for the vaccine have been created, 'to confirm that the vaccine has a protective effect by conducting a test using an appropriate animal model' and ' You will need two things to test with.

However, SARS-CoV-2 does not grow in wild mice and shows only mild symptoms in transgenic organisms having human ACE2, which poses a problem that animal experiments themselves are difficult. In addition, it is necessary to test the toxicity of the vaccine in rabbits, etc., but this must be done according to the standard of Good Laboratory Practice (GLP), and it will take 3 to 6 months to complete. However, it may be omitted if sufficient data has already been obtained with a similar vaccine created on the same manufacturing platform.

In addition, in order to keep the quality and safety of vaccines constant, manufacturing must be performed in a manner that complies with Good Manufacturing Practices for Pharmaceutical Products (cGMP), and requires dedicated equipment, trained staff, appropriate documents, and cGMP quality. Raw materials are required. While these processes need to be designed to be compatible with the SARS-CoV-2 vaccine, many vaccine candidates in the preclinical stage do not have such processes and must be developed from scratch.



After going through these processes, we are finally at the starting line for conducting clinical trials, but clinical trials start with a small phase 1 trial (Phase 1) and establish prescribing and usage to prove efficacy. Phase 2 trial (Phase 2) and finally a Phase 3 trial (Phase 3) demonstrating the safety and efficacy of the vaccine in a larger cohort. Regulatory approval will be granted once three clinical trials have shown effectiveness. However, some steps may be omitted in the event of an emergency during the COVID-19 pandemic.

And it will be necessary to have the production capacity to manufacture a large amount of cGMP quality vaccine, but it is considered difficult to make a vaccine that can be used by people all over the world as of April 2020. I will. In addition, it takes time to distribute and administer the vaccine, and most of the population needs at least a few weeks to get the vaccine. Furthermore, given that the effect of one vaccination is small and multiple vaccinations may be necessary, the second vaccination is given 3 to 4 weeks later, and 1 to 2 weeks after that, the immune effect is finally reached. Will appear. Taken together, the vaccine will not be available more than 6 months after the start of clinical trials and WHO will announce at the end of March 2020 that the vaccine will be at least 12-18 months ahead. Needs more time.

Given this, it is unlikely that a vaccine will be available to affect the current pandemic first wave. However, in order to prepare for the pandemic after the second wave, it is necessary to invest hundreds of billions of yen, develop a vaccine for this virus that can have a huge impact on the global economy, and build appropriate infrastructure There is.

in Science, Posted by logq_fa