THE END OF the year is fast-approaching and pharmaceutical companies and scientists have been working flat-out all through 2020 to develop a safe and effective vaccine for the virus that causes Covid-19.
Health officials have said the roll-out of a vaccine is the only thing that can ensure a full return to the normality people knew before this pandemic. Although the research is by no means complete, there is a strong sense of optimism in the medical and scientific community about the prospect of a vaccine in 2021.
Dr Fidelma Fitzpatrick, consultant and senior lecturer in microbiology at the Royal College of Surgeons (RCSI) has said the speed of pace in this race for a vaccine has been “amazing”.
“It normally takes between five to 10 years to bring a vaccine to market,” she told TheJournal.ie. “Usually one of the biggest hurdles can be funding, which doesn’t seem to be an issue now. Other issues can be manufacturing, logistics and scaling up. But it all starts in the lab with scientists in the pre-clinical stages.
“There is a huge amount of pre-clinical work before it gets to clinical trials – cell culture and animal testing before moving to tests on human. Most vaccine candidates stop at this point.”
After the pre-clinical stage and before a vaccine can be manufactured, it goes through three phases of clinical trials.
Phase One involves between 20 and 100 volunteers and the intention is to establish whether the vaccine is safe, whether it seems to work and whether there are any serious side effects. This phase will also look at how the size of the dose may be related to side effects.
Phase Two will involve several hundred people and aims to establish the most common short-term side effects and how the immune systems of those who have been given the vaccine respond.
Phase Three is the most crucial and the most thorough. It involves hundreds of thousands of people, some of whom will be given a placebo.
This phase examines how people who get the vaccine compared with those who get the placebo, whether it is safe and/or effective and it also aims to catch less common side effects as it involves a larger – and ideally more diverse – pool of people.
The results of the the trials go straight to regulators for examination after Phase Three and if the vaccine is approved based on the results, it can begin to be manufactured and administered.
The World Health Organisation has said 44 candidate vaccines are in clinical evaluation with 10 of those at the Phase Three clinical stage. These are:
- Sinovac, an inactivated vaccine, requires two doses;
- Siopharm/Wuhan Institute of Biological Products, an inactivated vaccine, requires two doses;
- Sinopharm/Beijing Instituate of Biological Products, an inactivated vaccine, requires two doses;
- University of Oxford/AztraZeneca, a non-replicating viral vector vaccine, requires one dose;
- CanSino Biological Inc/Beijing Institute of Biotechnology, a non-replicating viral vector vaccine, requires one dose;
- Gamaleya Research Institute, a non-replicating viral vector vaccine, requires two doses;
- Janssen Pharmaceutical Companies (Johnson & Johnson), a non-replicating viral vector vaccine, requires two doses;
- Novavax, a protein sub-unit vaccine, requires two doses;
- Moderna/NIAID, an RNA vaccine, requires two doses;
- Pfizer/BioNTech/Fosun, an RNA vaccine, requires two doses.
Some methods for making a vaccine are tried-and-true, while others remain experimental.
Inactivated ‘classic’ vaccines use a virus germ that has been killed or a weakened or “attenuated” strain that is virulent enough to provoke antibodies but not to cause disease. Other inactivated vaccines include polio, hepatitis A and rabies.
Viral vector varieties use other forms of live virus to deliver DNA into human cells, triggering an immune response. A measles virus modified with a coronavirus protein, for example, could be deployed against Covid-19.
The Johnson & Johnson vaccine uses a dose of a cold-causing adenovirus, modified so that it can no longer replicate. This is combined with a part of the new virus, SARS-CoV-2, called the spike protein that it uses to invade human cells.
‘Sub-unit’ vaccines, such as the Novacvax one, contain a fragment of the pathogen that it is derived from to produce an appropriate immune response. Other examples include the HPV and hepatitis B vaccines.
There are also experimental gene-based vaccines using DNA or RNA fragments.
How the trials are progressing
Results from many of these initial phases are encouraging, but until Phase Three data from these vaccines is published, it is too early to tell which ones could be used en masse.
Preliminary results from Sinpharm‘s trials, published in The Lancet journal, show it provoked an immune response. The company has said it anticipates antibodies from its jab to last between one and three years.
Recently the Sinovac vaccine, even though it hasn’t been approved for mass market distribution, was made available to some residents in an eastern Chinese city. Officials said the vaccine would be given to people aged between 18-59 with “urgent needs”. The vaccine requires two doses, given up to 28 days apart. The company has also already completed construction of a vaccine factory able to produce 300 million doses a year.
In September, trials on the coronavirus vaccine developed by AstraZeneca and Oxford University were paused after a UK volunteer developed an unexplained illness. The vaccine is one of the most advanced Western projects, having already been tested on tens of thousands of volunteers worldwide. British regulators and an independent review concluded the illness was not a side effect of the vaccine.
Trials resumed earlier this month in Japan but not the United States, where AstraZeneca is working with regulators. This week it was confirmed that a volunteer participating in clinical trials of the vaccine developed by Oxford University had died, but the man had received a placebo, rather than the active vaccine. The Phase Three trial is continuing.
During the summer, China’s military approved the CanSino vaccine for use within its ranks. Pakistan regulators also approved Phase Three testing for this vaccine in the country’s first ever clinical trial of this kind. However this vaccine uses a weakened human cold virus, adenovirus 5, and the Phase Two trial found high pre-existing immunity to this cold virus in participants reduced the immune response.
The Russian vaccine, developed by Gamaleya Research Institute, has already been used to vaccine high-profile Russians, including President Vladamir Putin’s daughter. Patients in early trials involving 76 people all developed antibodies, according to research published in The Lancet medical journal last week, while experts said the trials were too small to prove safety and effectiveness.
The Johnson & Johnson trial was paused recently over safety concerns after one patient became sick. Its Phase Three had started recruiting participants in September with a goal of enrolling up to 60,000 people. Pre-clinical testing on rhesus macaque monkeys that were published in the journal Nature showed it provided complete or near-complete protection against virus infection in the lungs and nose.
The US firm Novavax, which uses insect cells to grow synthesised pieces of the spike protein of the SARs-CoV-2 virus. Its early trials found the vaccine was well-tolerated and elicited robust antibody responses. The company has said it proved the efficacy of a flu vaccine using this same technology.
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Initial results from Moderna‘s trials indicate those who receive the vaccine produce antibody reactions from T-cells (a type of white blood cell). The company recently said it had successfully recruited ethnic minorities, older people and those with underlying conditions for its Phase 3 trial as it works to “develop a vaccine for everyone, including communities that have historically been under-represented”. It is aiming to file for authorisations soon after 25 November.
The Pfizer vaccine’s first two phases showed it produces antibodies and T-cell responses specific to the coronavirus protein. It has said it will apply for emergency authorisation in the US in late November if safety data pans out.
Dr Fitzpatrick said the pace at which these vaccines have been developed has been “remarkable” and she is optimistic about the development of a safe vaccine.
“It can take nearly 10 years to complete a vaccine and we have 10 of them at Phase Three already so that has to be cause for optimism.
“It’s so unprecedented, in October to have this number of candidates, anything can happen. Once we get to one or more being approved, the big question is where do you start? And how do you compare different trials? The WHO is now looking at trying to harmonise the methodology for vaccine makers to better facilitate that. We need to be able to compare like with like.
“Once we get that sorted we’re looking at the global distribution issues. Who do we prioritise, which areas of the world, which groups of people? How do we ensure we don’t overwhelm the cold chain? Because they have to be transported in fridges.”
She said it is likely that the first people to receive the vaccine will be healthcare workers and those in high-risk groups. However she said people should bear in mind that they will likely have to keep going with infection control measures for some time.
“The whole world isn’t going to get it at once,” she said. “This isn’t the be all and end all.”
“We will still have unknowns, like how long does it last and what we do in terms of people who just don’t respond to the vaccine, but there are other options such as giving monoclonal antibodies that might be open approach down the road.”
Fitzgerald said she acknowledges some people may be wary of getting a new vaccine – and one that has been developed so quickly.
Knowledge is power here. I always say to people to go and read the facts for themselves, go to reliable sources to inform yourself when you’re making a decision.
“There has never been a time when the entire world has been so focused on one type of vaccination programme so there will be huge scrutiny of the safety of these vaccines. The whole point of the Phase Three trials is to find any rare side effects that wouldn’t come through in the Phase One and Two trials.
“This isn’t going to get a free pass, there’s too much to lose, the entire world is looking at it so the regulators aren’t just going to push things through.”
- With reporting from AFP.