COVID-19 - Vaccines and Cures
Written on August 10th, 2020 by {"login"=>"jcbphc21", "email"=>"f20181005@hyderabad.bits-pilani.ac.in", "display_name"=>"Journal Club, BPHC", "first_name"=>"Journal Club", "last_name"=>"BPHC"}The novel coronavirus SARS-CoV-2, responsible for the disease COVID-19, which is known to affect the respiratory system, has wreaked havoc across the globe. More than 18.9 million patients have been affected by the virus, with nearly 709,511 COVID related deaths worldwide. Scientists and research groups around the world are now in a race against time to develop a vaccine to combat the disease. The World Health Organisation is now tracking nearly 26 potential vaccine candidates at various stages of clinical trials and as many as 139 candidates in under preclinical trials. The organization is not directly involved with the research and findings but is only constituting reasonable checks to verify the legitimacy of the data presented by the research groups.
COVID-19 is a new disease, and while most of the evidence points to natural infection with the virus generating protective immunity, significant gaps remain. Researchers know, for instance, that the mechanism of protection most likely will need to rely on a robust antibody response with neutralizing capacity, coupled with a balanced cellular response and cytokines (or immune proteins). In studies published so far, rhesus macaques infected with SARS-CoV-2 have shown to develop protective antibodies and resistance to reinfection. Previous studies from SARS-CoV in 2003 also showed that persistent antibody responses against the virus spike protein (the protein the virus uses to bind and invade a cell) and specifically against a part of the spike protein known as the receptor-binding domain, supported immunity.
Vaccines & Trials:
A vaccine is a biological preparation that provides active acquired immunity to people against certain infectious diseases. They are simple, safe, and effective against a wide range of disease-causing agents (pathogens). Vaccines contain agents that mimic these pathogens, often made from weakened forms of the microbe, its toxins, or its surface proteins. When introduced into the body of a host, they stimulate the body's natural immune system to identify the foreign microbes as a threat and eliminate them. They further prepare the body to identify and destroy any of the microbes associated with the disease in the future with the same vigor.
As the vaccines are being administered to millions of people, the standards for testing and receiving approval for mass usage is quite tricky. It usually takes a few years to devise, test, and successfully manufacture a vaccine. Owing to the ever-increasing number of cases around the world and with many countries reporting the uncontrolled spread of the virus, the process of vaccine development has been seemingly fast-tracked - providing reasonable relaxations on the studies - provided that the data is favorable, and there are as little side effects as possible.
Any vaccine usually undergoes four primary testing phases, including exhaustive preclinical trials or the preclinical stage, followed by testing on humans in three phases.
Researchers give the vaccine to animals in the preclinical stage of testing to see if it triggers an immune response.
In phase 1 of clinical testing, the vaccine is given to a small group of people to determine whether it is safe and to learn more about the immune response it provokes.
In phase 2, the vaccine is given to hundreds of people so scientists can learn more about its safety and correct dosage.
In phase 3, the vaccine is given to thousands of people to confirm its safety – including rare side effects – and effectiveness. These trials involve a control group that is given a placebo.
When it comes to human testing, ethics play a crucial role, and getting clearance from the government and various Ethics Boards is usually a very long-drawn process. Often, research groups present and revise many of their findings from the preclinical phase to get approval for the same. As mentioned before, this time around, most of the world governments have laid out committees in tandem with universities and labs from around the world to help expedite the process.
Present-day Scenario:
There are four frontrunners in the race to manufacture the world's first safe-to-use vaccine against COVID successfully: Oxford-AstraZeneca, the Chinese company Sinopharm, Chinese pharmaceutical giant Sinovac and US-based Moderna Inc. But as of the last week of July and August 1, more potential vaccine groups caught up with the trials.
Here's a small overview of the status of vaccines across different countries around the world:
ChAdOx1 nCoV-19 by University of Oxford, UK: Scientists at Oxford University's Jenner Institute and Oxford Vaccine Group, in partnership with AstraZeneca, a global pharmaceutical giant, developed this vaccine candidate in a record-breaking time of 3 months. It is delivered via a non-replicating viral vector (chimpanzee virus). It contains virions, protein spikes, similar to those found on the coronavirus, which help trigger a strong immune response from the body; thus, making it capable of producing antibodies to fight off the actual virus. The team has successfully finished preclinical and phase 1&2 trials and published their findings. It was observed that within 14 days of administration of the vaccine, they saw a spike in the T-cell (white blood cells that help attack SARS-CoV-2 virus) response and a very strong antibody response within 28 days after a booster dosage (antibodies neutralize the virus so that it cannot infect cells when initially contracted). The group has now started placebo-controlled randomized phase 2 trials in the UK and a few other nations and phase 3 trials in South Africa and Brazil.
Serum Institute of India has partnered with AstraZeneca and Oxford University to carry out phase 2 and 3 clinical trials in designated labs across the country after getting approval from the Drugs Controller General of India (DCGI), last week.
CoronaVac by Sinovac Life Sciences, China: China's Sinovac laboratory is working on a vaccine based on inactivated virus particles. They finished simultaneous phase 1 & 2 trials in China and Brazil and received approval for phase 3 trials. The group is still recruiting volunteers and is looking to conduct full-fledged studies on about 8870 subjects. It will be a double-blind placebo-controlled trial with participants being randomly administered 1:1 placebo and vaccine arms. This vaccine will be a two-dose vaccine.
Vaccine, ChiCTR2000034780 (No name) by Sinopharm, China: Wuhan Institute of Biological Products in collaboration with pharmaceutical company Sinopharm are working on developing an inactivated SARS-CoV-2 vaccine (Vero Cell). Again, it is a double-blind placebo-controlled vaccine with participants being subjected to two doses - on day 0 and day 14, respectively. The group conducted simultaneous phase 1 & 2 trials and will now be further conducting phase 3 trials on 5000 participants in Wuhan, Beijing, and Brazil.
Note: No data has been published by any of the Chinese research groups so far. They have only been giving updates about the status of their testing and production.
MRNA-1273 by Moderna Inc., USA: American biotech company Moderna is developing a vaccine candidate using mRNA (messenger RNA) that tricks the recipient's body into producing viral proteins. Participants were given 0.5-ml of the injection on days 1 and 29 of the study. They were divided into three groups and were given 25, 100, and 250 𝜇ml of the drug. A total of 45 participants enrolled in the first phase, out of which three participants did not receive the second dosage. One participant (25 𝜇ml groups) of these three, developed urticaria on both legs 5 days after the first vaccination and two others from the 250 𝜇ml groups, who missed the second vaccination window owing to isolation for suspected COVID-19. At the same time, the test results, ultimately negative, were yet pending. None of the participants had a fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever; one of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. The 25 μg dose seems to be promising, but one cannot make assumptions just yet though the T-cell response does appear to be showing good results.
The team has also completed their phase 2 testing with 600 participants and have now begun their phase 3 trials with 30000 participants. The results of both these trials are yet to be published. It is, however, interesting to note that no mRNA based vaccine has been approved so far. And Moderna hasn't brought any products to the market before.
COVAX-19 by Flinders University and Vaxine, Adelaide: Scientists at Flinders have been working overtime on a new vaccine, which shows promising results already. The vaccine is based on a recombinant spike protein with a trademark Advax adjuvant. The group has developed the vaccine model using AI technology with received support from the US National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID). The group claims that it is safe to use and has shown a strong antibody response in monkeys, ferrets, and rats. In their recent phase 1 trial, too, the group has seen good antibody response in humans. The group is positive that if things continue to remain this way, they would be able to produce the vaccine in the next 3-4 months.
Unnamed Vaccine by Gamaleya Institute, Russia: Contrary to most laboratories operating around the world, in what can be seen as a bold move, Moscow's Gamaleya Research Institute, has decided to go to production with their unnamed vaccine after just two-trials this month. They plan to get the vaccine registered by next week, making it the first effective registered vaccine against the coronavirus. It would be a conditional registration, which effectively means that the vaccine will be tested for another round after it is registered, in tandem with voluntary vaccinations of health workers all year-round.
News about the vaccine’s safety and efficacy is being taken with a little skepticism around the world. It is common knowledge that any vaccine, to be registered, has to undergo three phases of human trials with minimum side-effects. Shorter testing periods and smaller groups essentially mean that there are very little time and data to study the full effects of the vaccine and understand it’s reliability when administered to the masses. The vaccine would be administered in the form of an adeno-based non-replicating viral vector. The country has not released any further scientific data on its testing and methods to date. However, it says the data is currently being compiled and will available for peer review in early August.
COVAXIN by Bharat Biotech, India: India's first indigenously-developed vaccine against COVID, COVAXIN, is showing encouraging results after phase-1 of human trials. COVAXIN is one of the only two vaccines approved for human trials in India. It was developed by Hyderabad based firm Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR) and the National Institute of Virology. It is a whole virion inactivated vaccine. They started the trials with an estimated 1125 participants. They would carry out a randomized, double-blind, multicenter study while closely monitoring the response of the participants to the vaccine and the immunogenicity of the vaccine and its compatibility with the host cells.
There was a lot of criticism about the fast-tracking of the process and the safety and efficacy of the vaccine about it's scheduled August 15 release. ICMR later released a statement addressing a few of these issues: "ICMR's process is exactly in accordance with globally accepted norms to fast-track the vaccine development for diseases of pandemic potential wherein human and animal trials can continue in parallel." It is now being speculated that the vaccine will be released in a later part of the year.
Zy-Cov-D by Zydus Cadila, India: This is the second vaccine to have reached the trial phase in the Indian vaccine race. There are almost 14 more vaccine candidates currently undergoing preclinical trials across the nation. Zydus Cadila, a Hyderabad-based pharmaceutical company, has made strides to catch up with the leading vaccination trials. Their vaccine is designed to introduce a DNA that encodes for a viral protein response in the subjects, ordering the cells to produce the protein to fight off the virus, thus improving immune responses. The group has finished their phase 1 tests and is now pursuing phase 2 testing with about 1000 participants. So far, the results are similar to all other vaccines out there. There seem to be no side effects, and the group is now looking forward to getting favorable results from their next trial phases.
Other than the vaccine groups, Serum Institute of India, the world's largest vaccine manufacturing group (1.3 billion vaccines per annum), led by the Poonawal family, have partnered with three vaccines worldwide which include the likes of the Oxford vaccine (UK), NVX-CoV2373 by Novavax (USA), and Codagenix (USA) to carry out phase 2 & 3 trials in the country. This process provides a more varied dataset and will help understand how the vaccine responds to different populations and weather and temperature conditions. As of two weeks ago, the company received a green signal from the DCGI to conduct testing for Oxford's n-Cov-19 vaccine. They have also partnered with the Melinda Gates Foundation to produce 100 million vaccine doses per annum for India and other countries. They have also made a deal with Novavax to manufacture a billion doses of their vaccine for India and other middle-income countries.
Solidarity: A global quest to find a reliable treatment for COVID-19
With the immense pressure COVID - 19 has put on health systems around the world, the World Health Organisation considered the need to fast track trials and scale up to find an effective treatment for COVID. Hence, the inception of Solidarity. Solidarity is a global initiative that conducts randomized clinical trials to help the WHO find the proper cure for the virus. The program compares drugs against the standard of care to prove their effectiveness in treating patients. Enrolling multiple participants in a single randomized trial will quicken the process, thus helping the WHO compare many unproven treatments at once, instead of multiple small trials providing insufficient insights.
As of July, the committee submitted recommendations to the WHO to discontinue the hydroxychloroquine and lopinavir/ritonavir arm of the program's trials, as these drugs showed little to no improvement in the mortality of the hospitalized/critical care patients. This move only applies to the conduct of the trial in hospitalized patients. It doesn't affect the possible evaluation in other studies of hydroxychloroquine or lopinavir/ritonavir in non-hospitalized patients and post and pre-exposure treatment for COVID - 19.
Summing Up
Although there are many vaccine groups in this race and there are many groups even looking to get to production within the next few weeks, analysts and scientists worldwide believe that there would be no single winner in the vaccination field. Because, we need to cater to the population of the entire world, which means, implying that we would need billions and billions of doses of safe-to-use vaccines and clearly, one vaccine cannot achieve this. Even after scientists' and researchers' accelerated efforts, it could easily take another 6-9 months or even more before clinical trials are completed. After this, licensing boards would take time to review the results and reports before approving the vaccines fully. All of this indicates that it will be very long before a completely safe vaccine is available on the shelves.
Until then, what we, as responsible human beings, could do to help curb the spread is to follow health guidelines; by wearing masks, maintaining proper hygiene practices, staying indoors as much as possible, and, more importantly, listening to healthcare authorities and using a little common sense. With the lockdown relaxed, many countries saw a sudden spike in their COVID cases, causing second bouts of the virus in quite a few countries. A general disregard for rules and guidelines has been a significant factor in this. Governments and authorities must enforce stricter measures to make people more aware of the situation and help flatten the curve until a suitable cure is realized.