Vaccines Being Developed for COVID-19
There are at least 8 different approaches being used in the race around the world to find a vaccine for COVID-19.
The progress of the development of vaccines is often referred to as follows:
Phase 1 - safety trials:
Scientists will give small numbers of people the vaccine to test dosage and safety, as well as to confirm that it works and stimulates an immune response
Phase 2 - expanded trials:
Hundreds of people will be given the vaccine, and they will be split into groups by e.g. age and gender to see if the vaccine acts differently in them. These trials will also further test the vaccine;s safety and ability to stimulate the immune system.
Phase 3 - efficacy trials:
Scientists give the vaccine to thousands of people and wait and see how many people become infected compared to those who received a placebo. These trials can determine if the vaccine really does protect against COVID-19.
Early or Limited Approval:
China and Russia have approved vaccines without waiting for the results of Phase 3 trials.
In each country their own regulators will review the trial results before deciding whether or not to approve. However in a pandemic a vaccine may approve emergency use authorisation.
Some companies are combing phases to accelerate development.
Human Challenge trials
The UK is considering using challenge trials to speed up the approval of the Oxford/AstraZenca vaccine. Having had the vaccine, young and healthy volunteers would be exposed to the virus. An appropriate strain would be chosen and a dose of the virus which does not overload the immune system given. Many volunteers have signed up to the 1Day Sooner movement with 2,000 UK volunteers and 37,000 worldwide.
Edward Jenner first conducted a human challenge trial when he inoculated an eight-year-old boy with cowpox virus and then exposed him to smallpox back in the 18th Century. However, nowadays these would not meet the strict guidelines necessary for such a trial. Some scientists are very uncomfortable about infecting volunteers with a SARS COV-2 which can cause severe illness and for which there is not yet a highly effective cure.
As of 13th November using the New York Times Vaccine Tracker there are 54 vaccines in clinical trials on humans and at least 87 preclinical vaccines under investigation in animals.
The different approaches are explained below together with the status of some of the vaccines in further along in the trials.
1. Virus Vaccines
For a traditional vaccine, weakened viruses are grown in animal eggs or cells and the parts for the vaccine are extracted. This takes time as it can take 4-6 months to get the right antigens as some viruses change every year (e.g influenza). The modified version of the virus or pieces of it, in a solution, is injected into the body. When the immune system detects the antigens it makes antibodies that can find the virus anywhere inthe body and neutralise it. For inactivated virus vaccines the virus is made uninfectious using chemicals:
Phase 3 - Approved for Limited Use
The Wuhan Institute of Biological Products developed an inactivated virus vaccine which the state owned Chinese company Sinopharm put into clinical tests. Phase 1/2 showed the vaccine produced antibodies but some fever and other side effects in volunteers. Started Phase 3 in July in UAE and Peru and Morocco in August. In September emergency approval was given to use on health care workers.
Sinopharm also launched Phase 3 trials of a second inactivated virus vaccine developed by the Beijing Institute of Biological Products. Phase 3 trials are happening in UAE and Argentina. The UAE gave emergency approval to inject health care workers.
Sinovac Biotech in Beijing has started to test and inactivated version of SARS COV-2 in humans called CoronaVac. Sinovac previously developed a vaccine against SARS, the 2003 pandemic caused by a close cousin of the coronavirus, but stopped development at the Phase I stage as that outbreak came under control. In June the company announced that Phase 1/2 trials on 743 volunteers found no severe adverse effects and produced an immune response. Sinovac then launched a Phase 3 trial in Brazil in July, followed by Indonesia and Turkey. It has been reported that the Chinese government has given emergency approval for limited use. In September the CEO said worldwide distribution of the vaccine is planned for early 2021.
The Indian company Bharat Biotech designed a vaccine called Covaxin based on an inactivated form of the coronavirus in collaboration with the Indian Council of Medical Research and the National Institute of Virology. Studies on monkeys and hamsters showed protection against infection. The CEO has said it would be available no sooner than early 2021. On October 23rd the company announced that they were initiating a Phase 3 trial.
Researchers at the Institute of Medical Biology at the Chinese Academy of Medical Sciences, who have invented vaccines for polio and hepatitis A, started a Phase 2 trial of an inactivated virus vaccine in June.
As this process takes a long time labs are turning to gene-based vaccines on the hunt for one that will work against SARS COV-2.
2. Nucleic-Acid Vaccines
Here the genome from the virus is used to create a safe version of a disease-causing virus which will encourage the body to make antibodies to the real virus. A blueprint of select antigens is created which is made from the DNA or RNA molecules that hold the genetic instructions of how to make the antigen. These are injected into human cells which then use these instructions to make the protein. The antigen triggers the immune system to make antibodies.
The scientists want to find a way to train the human cells to make an antigen called the spike protein, this is what blows the virus to bind to the human cells and get inside. There are 3 ways of getting this spike blueprint into the cells, one is embedding it in a DNA plasmid, secondly by embedding it in a RNA lipid and thirdly using the common cold virus, this is called an adenovirus.
DNA plasmid vaccines
These have been made for veterinary uses but have not yet worked for humans. The problem being that the vaccines have had difficulty passing though a cells membrane. However, Inovio Pharmaceuticals in Plymouth USA launched trials on a similar basis to vaccinate against MERS another coronavirus This produced antibodies in vaccinated people.
Indian vaccine-maker Zydus Cadila has created a DNA-based vaccine delivered by skin patch. Phase 2 trials started August 6th.
Phase 1/2 Combined
AnGes, a Japanese Biotechnology company announced the start of safety trials on a DNA-based vaccine on June 30th, developed in partnership with Osaka University and Takara Bio. They are planning a Phase 3 trial by the end of the year.
These work by embedding the RNA in lipids that are injected into the body and as lipids are fatty molecules that can easily pass into cells, this might work better. However, this vaccine is less stable than DNA -plasmid vaccines as common enzymes in the body can degrade them. Also heat can affect them too so they need to be kept cold which might cause problems in poor countries with high temperatures. Some RNA vaccines are in clinical trials for other viral illnesses such as rabies, HIV and Zika.
Moderna in Cambridge Massachuettes began small human trials on March 16th, on 8th May it announced that the vaccine had produced antibodies in its small trial.. Moderna published promising Phase I results on July 14, and Phase 3 trials begun on July 27. They are enrolling 30,000 healthy people over 89 sites in the US. They plan to wait until a significant number became sick with Covid-19 and then see how many had been vaccinated which may take until late 2020 or early 2021.
BioNTech, a German company, is collaborating with New York-based Pfizer and the Chinese drug-maker Pharma to develop an mRNA virus. On November 9th they announced that preliminary data showed that the vaccine was 90% effective. In July they launched phase 2/3 trials with 30,000 volunteers in US, Argentina, Brazil and Germany. On 12th September they expanded their US trial to 43,000 people. US have contract for 100 million doses plus option for 500 more. Japan 120 million doses and EU 200 million doses. Like most vaccines it requires 2 doses. They are expected to apply for emergency use Authorisation by the end of November and they can manufacture over 1.3 billion doses worldwide by the end of 2021.
In June CureVac launched their Phase 1 trials. In September they gave injections to volunteers in Panama and Peru for Phase 2 and plan Phase 3 by end of the year. They say that their German facility can make hundreds of millions of vaccine doses a year and hope to gain approval in 2021. CureVac have got together with Elon Musk's company Tesla to create mRNA "micro factories" which could be deployed around the world to make billions of doses.
Imperial College London researchers have developed a "self amplifying" RNA vaccine, which boosts production of a viral protein to stimulate an immune response. Phase 1/2 trials started on June 15, and they have partnered with Morningside Ventures to manufacture and distribute the vaccine through a new company called VacEquity Global Health. The researchers expect to know if the vaccine is effective by the end of the year.
Arcturus Therapeutics in California and Duke NUS Medical School in Singapore have developed an mRNA vaccine with a 'self replicating' design that leads to a greater production of viral proteins. Tests on animals showed it protected them against infection. Phase1/2 trial launched in August in Singapore.
RNA- and DNA-based vaccines are safe and easy to develop as producing them involves making genetic material only not the virus. But they are unproven and no licensed vaccines currently use this technology.
3. Viral Vector vaccine
The virus DNA blueprint is inserted into a common cold or measles virus, this then infects human cells. Only problem is if the human immune system recognises some adenovirus and attacks them before they get in. Therefore they need to use a an adenovirus that the body is unlikely to have been seen before.
Once a vaccine is deemed to work it is then assessed in animals to see if it works there and is safe. Then people are tested in small groups and then in increasingly large numbers.
Phase 3 Approved For Limited Use
The Chinese company CanSino Biologics developed a vaccine based on the Ad5 adenovirus, in partnership with the Institute of Biology at China's Academy of Military Medical sciences. In May they published promising results from a Phase 1 safety trial and in July said that Phase II trials showed that the vaccine produced a strong immune response. The Chinese military approved it on June 25th for a year as a "specially needed drug" for soldiers. In August Phase 3 trials began in countries including Saudi Arabia, Pakistan and Russia.
Phase 3 Approved For Early Use
The Gamaleya Research Institute, which is part of Russia’s Ministry of Health, launched a Phase I trial in June of a vaccine known as Gam-COVID-Vac Lyo. It is a combination of two adenoviruses, Ad5 and Ad26, both engineered with a coronavirus gene. In August the vaccine renamed as Sputnik V was given a "conditional registration certificate" which would depend on positive results from Phase 3 trials 40,000 volunteers. In September they announced that in the Phase 1/2 trials Sputnik V produced antibodies and mild side effects. On November 11th they announced that preliminary evidence from Phase 3 trials showed that the vaccine was effective and demonstrated 92% efficacy.
Oxford University began human trials in April in up to 500 people. It is in development with British-Swedish company AstraZeneca and is based on a chimpanzee adenovirus called ChAdOx1. In an animal trial the vaccine was not able to stop the virus from getting into the rhesus macaque monkey, however it did work against pneumonia. The trial suggests that, while not stopping the virus, it may be partially protective. In Phase 1/2 trial no severe side affects were detected and it was found that the vaccine raised antibodies against coronavirus. Phase 2/3 trials are occurring in England and India and Phase III trials in Brazil, South Africa and United States. In September a volunteer developed transverse myelitis which is a form of inflammation and global trials were paused for investigation. All trials have resumed except for the US while the FDA investigates. The company says their capacity is for 2 billion doses and India's Serum Institute has already produced millions of doses to be used in trials,
A decade ago, researchers at the Beth Israel Deaconess Medical Centre in Boston developed a method for making vaccinations out of a virus called Adenovirus 26, Ad26 for short. Johnson & Johnson developed vaccines for Ebola and other diseases with Ad26 and have now made one for COVID-19. The Vaccine provided protection in animal experiments on monkeys. They launched Phase 1/2 trials in July and Phase 3 with up to 60,000 volunteers in September with hopes of producing up to a billion doses in 2021.
4. Protein based vaccines
The vaccines involve injecting coronavirus proteins directly into the body. Protein shells that mimic the coronavirus's outer coat can also be used.
Twenty eight teams are working on vaccines with viral protein subunits. Similar vaccines against SARS virus protected monkeys against infection but haven't been tested on people yet.
These work by injecting immune stimulating molecules along side the vaccine.
Virus like particles (VLP)
Empty virus shells mimic the coronavirus structure. They are not infectious as they lack any genetic material. There are 5 teams working on this type of vaccine but they are very difficult to manufacture.
The US company Novavax has developed a way to attach proteins onto microscopic particles. They have created vaccines for a number of different diseases using this platform; their flu vaccine finished Phase 3 trials in March. The company launched COVID-19 vaccine trials in May, with Phase II in South Africa in August and then Phase 3 on 15,000 volunteers in the UK in September and a larger trial in the US is planned for November. If the trials succeed, Novavax expects to deliver 100 million doses for use in the United States by the first quarter of 2021 and the Serum Institute of India have said that they would be able to produce 2 billion doses a year.
Phase2/3 Combined Phases
Canada-based Medicago, partly funded by the cigarette maker Philip Morris, uses a species of tobacco to make vaccines. They deliver virus genes into leaves, and the plant cells then create protein shells that copy viruses. In July, Medicago started Phase 1 trials on a plant-based Covid-19 vaccine together with adjuvants to boost the immune system’s response to the viral proteins. They found that an adjuvant made by GSK produced promising levels of antibodies. On Oct. 23, they agreed toto supply Canada with 76 million doses. A Phase 2/3 trial of the vaccine began on Nov. 12.
In July, Anhui Zhifei Longcom, a company from China began Phase 2 trials for a vaccine which is a combination of viral proteins and an adjuvant that stimulates an immune response. The company is part of Chongqing Zhifei Biological Products and has partnered with the Chinese Academy of Medical Sciences.
Finlay Vaccine Institute in Havana announced Phase 1/2 clinical trial. The vaccine called Soberana , contains part of the spike protein , called RBD, along with an adjuvant to boost the immune response.
Vector Institute in Russia trial for a vaccine called EpiVacCorona. Vaccine contains small portions fo viral proteins (peptides).
Sanofi has also produced a vaccine based on viral proteins which they launched the trials for in September. They produced the proteins with engineered viruses that grow inside insect cells. GSK supplemented these proteins with adjuvants that stimulate the immune system. They plan to start Phase 3 in December. IN addition to deals with US, European Union and Canada they have agreed to provide much of its global supply to COVAX.
A spinoff from University of Oxford, SpyBiotech announced at Phase1/2 trio lain Australia. Vaccine was created from a mixture of proteins. Some proteins from Hepatitis B viruses assemble themselves into hollow shells which are decorated with coronavirus spike protein. The Serum Institute of India has licensed the technology from SpyBiotech and is running the trials.
After the SARS epidemic in 2002, Baylor College of Medicine began developing a vaccine that could prevent a new outbreak. Despite promising early results, support for the research disappeared.As the coronaviruses that cause SARS and Covid-19 are very similar, the researchers revived the project in partnership with the Texas Children’s Hospital. They have found that the Covid-19 vaccine produces antibodies in mice. The Indian company Biological E licensed it in August and launched Phase 1/2 trial in November. Clinical trials are planned for December.
5. Repurposed Vaccines
Researchers are attempting to adapt or reuse vaccines already in use for other diseases that may also protect against COVID-19.
The Bacillus Calmette-Guerin vaccine was developed in the early 20th century as a protection against tuberculosis. The Murdoch Children’s Research Institute in Australia is conducting BRACE, a Phase 3 trial to see if the vaccine partly protects against COVID-19.