About ten coronavirus vaccines are now in Phase 3 trials, the last stage of efficacy testing before a vaccine can be fully deployed in the wider population. Below we profile in brief the developers and platforms the candidate vaccines use. This updates our earlier archived post about the most promising candidate vaccines and the platforms — from RNA to inactivated COVID viruses — that they use.
- In pre-clinical/Phase 1 trials, vaccine candidates are tested in animals and then small numbers of people to test safety and dosage.
- In Phase 2 trials, vaccines are given to larger groups of people to check immune stimulation and whether different groups (e.g. defined by sex, ethnicity or age) show different responses.
- In Phase 3 trials, vaccines are given to tens of thousands of people in an epidemic situation, with one large group getting the real thing and another a placebo. If the vaccine works, those given the placebo will be the only ones getting infected.
Experts have emphasized that transparency is crucial in terms of how vaccines are developed and tested, especially given that the latest polls show declining public trust in potential COVID vaccines — an extremely worrying sign if we are to get wide enough uptake of a vaccine to halt the pandemic.
The upshot: Phase 3 trial data has begun to become available (see below), meaning that large-scale manufacturing of the lead candidate vaccines can begin in parallel. Our guess is that the first doses could be administered before the end of 2020 — quite an extraordinary result if it pans out, given that vaccines traditionally take over a decade to develop.
As our colleague Justin Cremer reported, BioNTech/Pfizer scored a big win in the initial results of their Phase III trials. According to data released on 18 November, their mRNA-based vaccine is at least 95% effective in preventing infection with COVID-19 after tests in more than 43,000 people. The testing regime involved an initial shot followed by a booster. Importantly, the study monitors have not reported any serious safety concerns.
mRNA vaccines are an entirely new technology, which use messenger RNA to get human cells to produce COVID viral proteins in the body to trigger an immune response rather than injecting them from outside. Phase 1 and 2 trials produced promising data, with the subsequent results reported in Nature in August. mRNA vaccines have the advantage that they should be easy and quick to tweak should the virus mutate significantly.
With the US and many countries inEurope in the midst of a devastating coronavirus second wave, the timing of a vaccine release is of intense interest. The companies say they “expect to produce globally up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021”. Many countries, like the UK, which have already ordered millions of doses of the vaccine in advance, are already planning who will be the first to receive it – the elderly and those working in the health care sector. Pfizer says it will submit for FDA emergency use authorization around the third week of November.
On 16 November Moderna also reported preliminary Phase III data – and the news was just as good as for the Pfizer vaccine, with an efficacy rate of around 95% in preventing COVID-19. Both vaccines use similar mRNA technology.
This interim analysis was based on 95 cases, of which 90 cases of COVID were observed in the placebo group versus 5 cases in the group which was administered Moderna’s mRNA-1273 vaccine. This equates to a vaccine efficacy rate of 94.5% with a p value of <0.0001, meaning a less than 1 in 10,000 chance that these results would have happened by chance only. Importantly, of 11 severe cases of COVID-19, none occurred in the vaccinated group, suggesting that the vaccine may protect against severe disease for those who do get infected. No significant safety concerns were reported.
Moderna says that it will apply for ’emergency use authorization’ from the FDA “in the coming weeks”, which will be informed by the full trial data due to be released when the trial passes its completion milestone. The company says it will have 20 million doses of mRNA-1273 ready to ship by the end of 2020, and that it remains on track to manufacture 500 million to 1 billion doses globally in 2021.
Another mRNA player is CureVac, which posted promising Phase I results in early November. Although it is some way behind both Moderna and Pfizer, it claims to have produced a better immune response and will be well-positioned to deliver large numbers of lower-dose vaccines in the second quarter of 2021.
AstraZeneca’s prospective COVID-19 vaccine uses a weakened form of a common cold virus (called an adenovirus) that usually infects chimpanzees. It is genetically altered to carry some of the code for key proteins in the SARS-CoV-2 virus, thereby eliciting a protective immune response in humans.
This vaccine is now in Phase 3 trials in the United Kingdom, Brazil, South Africa and the United States. Preliminary data released on 23 November suggested that – for one dose regime at least – 90% efficacy could be found, while averaged over two dose regimes the efficacy rate was 70%.
Earlier, on 16 November the Oxford team announced results of a Phase 2 trial which showed that the ChAdOx1 nCoV-19 vaccine performed well in stimulating an immune response in older adults. The results, published in The Lancet, showed both T-cell and antibody responses.
AstraZeneca says it is ramping up towards a global production capacity of 3 billion doses in 2021 on a rolling basis, assuming regulatory approval is achieved – it will start by seeking an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability for developing countries. Unlike the mRNA vaccines produced by Moderna and Pfizer, which require extreme deep freeze, the Oxford vaccine can be stored, transported and handled at normal refrigerated conditions (2-8 degrees Celsius/ 36-46 degrees Fahrenheit) for at least six months and administered within existing healthcare settings.
Sinovac and Sinopharm
These Chinese COVID vaccine candidates use the tried-and-tested method of inactivated viruses as a vaccine. Sinopharm is currently running a Phase 3 trial among 15,000 people in Abu Dhabi, while Sinovac is running a trial in 9,000 health care professionals in Brazil. This trial was halted on 10 November due to the death of a participant; however when this was found to have been a suicide the trial was restarted the following day. Phase 1/2 trial results were published in The Lancet Infectious Diseases in mid-November – the study authors reported that the vaccine was safe and “generated robust antibody responses” in patients.
In November the state-owned company Sinopharm said that out of 56,000 people who had received its vaccination and travelled abroad, none had been infected with coronavirus – anecdotal evidence to complement formal Phase III trials currently ongoing in UAE, Egypt, Bahrain, Peru and Morocco. Hundreds of thousands of Chinese have already received the vaccine, according to reports.
Johnson & Johnson
Like the Oxford vaccine, J&J’s vaccine also uses genetically-engineered adenovirus as a vector, a technology it has already successfully deployed in its fully approved Ebola vaccine. In September the company launched Phase III trials with 60,000 volunteers across three continents to study the efficacy of its COVID vaccine versus a placebo. The company is scaling up manufacturing and plans to have a billion doses available next year, which could be rolled out after ’emergency use authorization’ is achieved in early 2021. The vaccine, which is catchily titled JNJ-78436735, is the first single-dose COVID-19 candidate to enter Phase III trials. All the other candidates are likely to require an initial shot followed by a booster.
Russia’s ‘Sputnik V’
Russia, of course, already claims to have won the vaccine race. Launched as always with an eye to Soviet-style propaganda, the so-called Sputnik V vaccine hadn’t yet completed standard Phase 1 and 2 testing and Russia’s regulator later walked back on the announcement. The test results have since been published in the Lancet and look reassuring — the safety profile was good and a strong immune response was seen. However, some researchers have since raised questions about apparent duplications in the data and other concerns.
The vaccine is another adenovirus vector approach and is being developed by the Gamaleya Research Institute, part of Russia’s ministry of health. A 40,000-person formal Phase 3 trial is now underway in Russia.