Vaccines Being Developed for COVID-19
Vaccines aim to get the body to produce an immune response to block or kill the virus by exposing the body to an antigen that doesn't caused disease. There are at least 8 different approaches being used in the development of vaccines in the fight against COVID-19.
The chart below shows the spread of the different types of vaccines in development in early 2020:
Around the world development of vaccines has continued at a pace. On 28th April 2021 the situation was as follows:
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.
Trials can be paused or abandoned if worrying symptoms are observed.
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 infectiousness of the virus is removed using chemicals:
The virus vaccines approved or in Phase 3 are as follows:
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 February 2021 China approved the vaccine for general use. The UAE has approved it for limited use. Efficacy from the phase 3 trials has not yet been published.
Sinopharm also launched Phase 3 trials of a second inactivated virus vaccine developed by the Beijing Institute of Biological Products. In December 2020 Sinopharm announced an efficacy of 79.34% and the Chinese government approved its us. Following emergency approval in December the U.A.E gave it full approval. In January Hungary approved it and became the first European country to use a Chinese vaccine.
Sinovac Biotech in Beijing. 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. In July 2020 it gained Chinese approval for emergency use. In January 2021 Indonesia, Turkey and Brazil authorised the vaccine for emergency use. In February 2021 the Chinese gave it conditional approval. On April1 the company said that its capacity had increased to 2 billion doses.
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. In January the Indian government gave it emergency authorisation. In April it was reported that the vaccine had an efficacy of 78% against mild moderate and severe Covid-19. They also found that it had an efficacy of 70% against Covid-19 without symptoms suggesting that it can block the spread of the virus.
In Kazakhstan The Research Institute for Biological Safety Problems (RIBSP) has developed a vaccine made from inactivated coronaviruses called QazVac which started Phase 3 trials in March. There are not any published results from the trial but the vaccine was authorised in April and has just started being administered to the public.
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 3 trial of an inactivated virus vaccine in December in Brazil and Malaysia.
Shenzhen Kangtai Biological Products will start a Phase 3 trial of a vaccine on inactivated coronaviruses starting in May 2021.
Valneva a French vaccine maker created VLA2001 a vaccine from chemically inactivated viruses using and adjuvant from Dynavax and is the only inactivated virus vaccine being developed in Europe.With so many vaccines available the vaccine is to be compared against AstraZeneca rather than a placebo.
An Iranian company called Shafa Pharmed Pars has developed an inactivated coronaviruses based vaccine called COVIran Barekat which began Phase 3 trials on April 25.
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.
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.
RNA vaccines which have been approved or are in Phase 3 trials are:
In January 2020 BioNTech, a German company started looking at a genetic molecule called messenger RNA (mRNA). They created the genetic instructions for building the spike coronavirus protein. When injected into cells the vaccine causes the cells to make spike protein to provoke an immune response. In March 2020 BioNTech got together with New York-based Pfizer to scale up research. On November 9th they announced that preliminary data showed that the vaccine was 90% effective. By Dec 2nd the UK gave emergency authorisation and on Dec 31st the WHO gave the vaccine Emergency Use Listing. It has proven a highly effective but is a challenging vaccine to distribute as it has to be stored at -70 deg C (-94 F). The vaccine works well against the variant of Covid-19 first indentified in Brazil (P.1) but was less effective against the variant first identified in South African variant (B.1.351). The vaccine has now been approved for use or emergency use in many countries around the world.
Moderna in Cambridge Massachuettes began small human trials in March 2020 on its vaccine which was also made from mRNA. In November researchers estimated that it had an efficacy rate of 94.1% and by December the FDA gave emergency use authorisation for the vaccine in the USA. The vaccine has approval for use and emergency use in many countries around the world.
Another mRNA vaccine CureVac is being developed in Germany. Currently in Phase 3 trials.. 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. In November 2021 they announced that the vaccine could be kept in a refrigerator at 5 degrees C (41 F) whereas Pfizer and Moderna need to be kept frozen.
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 and this produced antibodies in vaccinated people.
Indian vaccine-maker Zydus Cadila has created a DNA based vaccine delivered by skin patch. Phase 3 trials started January 2021.
Phase 2/3 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 moved to Phase 2/3 trials in December.
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.
Viral vector vaccines that have been approved or are in Phase 3 trials are:
The Gamaleya Research Institute is part of Russia’s Ministry of Health, launched a trial of a vaccine known as Gam-COVID-Vac which was a combination of two adenoviruses, Ad5 and Ad26, both engineered with a coronavirus gene. The vaccine renamed as Sputnik V and in November 2020 they announced that preliminary evidence from Phase 3 trials showed that the vaccine was effective and demonstrated 92% efficacy. The vaccine was offered to Russians in a mass vaccination campaign in November and by December Belarus also authorised its emergency use. It has early use in Russia and emergency use in many countries around the world.
Oxford University began human trials in April 2020 in up to 500 people. It is in development with British-Swedish company AstraZeneca and is based on a chimpanzee adenovirus called ChAdOx1. With a 76% efficacy and only needing refrigeration, it is being produced and distributed at a low price to be used widely around the world. In December 2020 the UK and Argentina both gave emergency authorisation and in February the WHO recommended the vaccine for emergency use adults 18 or over. In March Brazil gave full approval and COVAX began delivering millions of doses to low and middle income countries. In February South Africa halted the use of the vaccine as a small trial failed to show that it protected against the B.1.351 variant. In March European regulators became concerned about a small number of blood clots following the vaccine and concluded that this was a very rare side effect. It emphasised that the vaccine was effective and the benefits outweighed the small risk. Oxford and AstraZeneca are researching combine vaccines and a new version tailored to the B.1.351 variant and are testing a nasal spray version. The vaccine is approved for use in Brazil and for emergency use in many countries around the world. Denmark has stopped its use.
The Chinese company CanSino Biologics developed a vaccine called Convidecia based on the Ad5 adenovirus, in partnership with the Institute of Biology at China's Academy of Military Medical Sciences. In February 2021 China announced the approval of the vaccine for general use. The company announced an efficacy rate of 65.28% but in April said its efficacy could drop over time. In March is won approval for a trial of an inhaled version. The vaccine has approval for emergency use in Chile, Hungary, Mexico and Pakistan.
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. It has been shown to be safe and effective with one dose and gained emergency use authorisation from the FDA in February. In April the US paused of the vaccine whilst it looked into rare blood clots, the vaccine now has a warning added to it that you women might have a slight risk of the blood clots.
ReiThera and Italian company is now in Phase 2/3 trials of a vaccine called GRad-COV2 based on an adenovirus that infects gorillas.
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 protein-based vaccines that have been approved or are in Phase 3 trials are as follows:
EpiVacCorona was approved by Russia in October and was developed by the Vector Institute which is a biological research centre. It has also been approved for use by Turkmenistan.
In July 2020, Anhui Zhifei Longcom, a company from China and the Institute of Medical Biology at the Chinese Academy of Medical Sciences began Phase 2 trials for a vaccine, ZF2001, 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. China approved the vaccine for emergency use in March.
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 2020. In March the UK trial gave an efficacy rate of 96% against the original COVID-19 virus, but in South Africa against B.1.351 it was only 49%. The trial involving 30,000 people is expected to give results in April and they expect to get authorised by the FDA in May. In April Novavax said that they could reach a production goal of 150million doses by the third quarter of 2021.
Finlay Vaccine Institute in Havana have developed a vaccine called Soberana 2 which contains part of the coronavirus spike protein fused to a standard Tetnus vaccine to make it stableed to thealong with an adjuvant to boost the immune response. The Phase 3 trial has just started in April 21.
Medicago is a Canadian based company partly funded by the cigarette maker Philip Morris and 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, they 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. Phase 3 trials began in March.
After the SARS epidemic in 2002, Baylor College of Medicine began developing a vaccine. As the coronaviruses that cause SARS and Covid-19 are very similar, the researchers restarted the project with the Texas Children’s Hospital and 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 combining the viral proteins with an adjuvant made by Dynavax. In April they announce Phase 3 trials and the US government have said it would fund an expansion of manufacturing to allow them to produce at least 1 billion doses by end of 2022.
Clover Biopharmaceuticals developed a vaccine containing the spike protein from coronaviruses and is being tested with adjuvants made by GSK and Dynavax. It has recently moved to a Phase 2/3 trial with the Dynavax adjuvant.
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.