Coronavirus Research Tracking - 24 July

Highlights of emerging COVID-19 research from the Science Media Centre team.

In this week’s Research Tracker the focus is on papers reporting the results of Phase 1 and/or 2 clinical trials of four vaccines.

The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre. 

Context

Trials of new drugs, vaccines (and other medical treatments) usually go through several stages or phases of testing.

  • Pre-clinical trials of drugs and vaccines involve tests on animals to determine potential effectiveness and toxicity.

  • Phase 1 trials involve tests on relatively small numbers of healthy human volunteers to see if the treatment causes significant unanticipated reactions.

  • Phase 2 trials have more volunteers (tens to hundreds). These usually match some of the characteristics (such as age and health) of those for whom the drug or vaccine is intended. This helps to better understand safety.

  • Phase 3 trials involving hundreds or thousands of people are used to see how well the drug or vaccine works on those who have the disease or become infected.

These trials usually take many years. With Covid-19 that time line has been considerably reduced by shortening and overlapping some phases of development, and by preparing for large-scale manufacture and distribution earlier. Shorter regulatory approval timelines are also possible for emergency use purposes. 

For example, Moderna has only just published the results of a Phase 1 trial but is already starting on Phase 2 and Phase 3 trials. The latter involves recruiting 30,000 people to be part of the trial.

An article in Nature provides an overview of the different types of vaccines, and some of the challenges and benefits for the new types.

Some researchers are cautioning that speed is good but hastiness isn’t. The trials shouldn’t cut corners that make vaccines less safe.

Immunity 101 video

If you have a spare 8 minutes here’s a helpful video explaining immunity for non-immunologists.

Four vaccines

The recent papers involve four vaccines of two types. Two (from CanSino Biologic and Oxford University [in partnership with AstraZeneca]) involve using disabled adenoviruses to introduce the SARS-CoV-2 spike protein, which will hopefully stimulate a strong immune reaction. 

The other two (from BioNTech and Moderna) involve a more novel type of vaccine that delivers RNA from the virus, wrapped in a lipid shell, to get cells of those vaccinated to produce all or part of the spike protein to trigger an immune response.

Many other vaccines are also in clinical trials, but their results have not been published yet.

The adenovirus-based vaccines

CanSino Biologics’ Ad5-nCoV vaccine is using an existing human adenovirus - adenovirus 5 - that causes colds. It has been deactivated so it can’t reproduce, and has the full length sequence of the SARS-CoV-2 spike protein gene. 

A challenge with using this adenovirus as a vector is that many people (some estimates are up to 70%) will have been infected by this previously, so that an immune response to the Covid-19 protein may be weaker.

The University of Oxford’s ChAdOx1 nCoV-19 (now being called AZD1222) uses an inactivated chimpanzee adenovirus that produces the Covid-19 spike protein. ChAdOx1 was used previously to develop a vaccine against MERS, but trials weren’t completed because the epidemic ended.

The RNA vaccines

RNA vaccines are a relatively new development. None have yet been approved for human use, although several are being developed.

The BioNTech/Pfizer BNT162b1 (three other variants are also being developed) has the receptor-binding domain of the spike protein RNA sequence encapsulated for delivery in a lipid nanoparticle. The RNA has been modified to make it more stable and able to be translated more efficiently.

Moderna’s mRNA-1273 contains the spike protein sequence and is also in a lipid nanoparticle. Its RNA is also modified for better stability. 

The Trials

Some of the trials are only Phase 1, while some combine aspects of Phases 1 & 2.

Ad5-nCoV (CanSino): Two papers have been published. The first, published in The Lancet in May, reported on trials testing three doses (low, medium and high) of the vaccine, with 36 people in each group receiving single injections.

The second (published this week in The Lancet) involved two single injection doses (253 people for the medium dose from the first trial, 129 for the low dose), along with a placebo (126 people; a saline injection). Results are reported up to 28 days after vaccination.

AZD1222 (Oxford):  543 volunteers received a single dose and 534 others received a meningococcal vaccine as a control. A group of 10 received a second dose of AZD1222 28 days later. Results reported up to 56 days after (first) vaccination.

BNT162b1 (BioNTech): Two papers, not yet peer reviewed, report on two trials, the first in the US and the second in Germany. Four dose levels were tested, with 12 people in each group. Three groups were given two injections 22 days apart, and one group received a single higher dose. Nine people were given a placebo (probably saline, but not specified). Results reported up to 28 days after first vaccination.

mRNA-1273 (Moderna): The published results involved three different concentrations of the vaccine with two injections given 28 days apart. Fifteen people were included in each group. Results reported up to 43 days after vaccination.

The Science Media Centre has expert reactions to the CanSino and Oxford papers.

What the results show

These trials were intended to demonstrate safety and the ability of the vaccines to produce an immune response. They are not intended to demonstrate how effective they are in preventing infection or reducing the severity of infections.

Safety

All four vaccines appear relatively safe at this stage, allowing trials to continue. Mild or moderate headaches, fever, and/or muscle pain were the most common symptoms, but didn’t last too long (days not weeks). Many experienced reactions to the vaccinations, with some of the more severe symptoms often, but not always, associated with higher doses.

Reactions can still be quite debilitating for several days, as this first person account describes.

A caveat to safety is that relatively small numbers of people were given the vaccines, all were healthy, and mostly between 18 and 55 years old. In addition, most of the trial volunteers have been white and from Europe or the USA. CanSino tested their vaccine on chinese people, and included some people over 55.

Immune reactions

All the vaccines seem to produce reasonable binding and neutralising antibody responses that are specific to the virus’ spike protein (or the receptor binding site of it). The levels can be variable, but they are usually similar to, or higher than, those in people recovering from Covid-19. 

The four vaccines all appear to stimulate, to some degree, T cells. Good stimulation of T cells is critical for more effective immune responses. However, as an article in Nature notes, we don’t yet have a good understanding of the type of immune response profile(s) that indicate good protection.

These are encouraging results that indicate the vaccines are working as intended. Unintended immune reactions were not reported, although only small numbers of people were tested.

Results can’t be compared between studies because of different methods used. It isn’t possible to determine at this stage if some of the vaccines are likely to be more effective.

Trial Differences

Age and Pre-existing Immunity

CanSino’s adenovirus trials have two main differences from the others. This first is that they included some older people (over 55). This is important since those most at risk from Covid-19 are older.

The second paper on the Ad5-nCoV vaccine reports that immune responses were lower for older people. This isn’t a surprise, but means that if the vaccine is eventually approved it may not be suitable for older people, or they may need a larger dose or a booster shot.

In the second trial 52% of participants had high pre-existing immunity and 48% had low or no pre-existing immunity to adenovirus 5.

The paper also reported that those who had high levels of pre-existing immunity to adenovirus 5 produced neutralising antibodies at half the rate as those with no or low levels of pre-existing immunity. They did, though, still have higher levels of neutralising antibodies than those in the trial not given the vaccine. The implications of this will be studied in subsequent trials.

T cell responses

While all reports describe T cell responses, the Moderna and BioNTech papers perform more detailed analyses of specific CD4+, and in the case of BioNTech, CD8+ cells. Studies at this level may provide a better indication of the possibility of longer term immunity.

The BioNTech and Moderna analyses report encouraging indicators for inflammatory immune responses.

Results from the BioNTech German trial, although the number of people involved is small, provide some confidence that this vaccine (in these doses) does not result in “antibody-dependent enhancement”, where the vaccine stimulates the immune system to cause more damage.

Conclusion

SARS-CoV-2 has only been known for eight months. Having four different vaccines providing encouraging safety and immune response results in early clinical trials is a great achievement. But there is still months more research to determine if these, or other vaccines, provide widespread effective immunity (short or long term), or moderation of Covid-19 symptoms.

Looking ahead, the logistics of manufacturing and supplying billions of doses of effective vaccines also needs to be well planned and managed. Vaccines will also need to be affordable for all. And people will need to want to be vaccinated.

Challenge Trials

A report in Science provides the reasons why some young people are interested in being involved in “Challenge Trials” to test vaccines, where they are injected with the virus after being vaccinated. A concern is that if the vaccine is ineffective and there is no effective alternative treatment then some of those being challenged may suffer serious health consequences.

Other SMC resources