So, what about vaccines where there is published data? Well so far there is only one vaccine that I am aware of where data has been published in a peer review journal, and that is the Oxford vaccine made by AstraZeneca (based in Cambridge!) in collaboration with Oxford University in the UK (don’t Oxford and Cambridge normally compete in boats against each other?).
What is the Oxford vaccine?
The Oxford vaccine (ChAdOx1 nCoV-19) is a combination of the SARS CoV2 spike protein and a chimpanzee adenovirus, which has been modified so that it can’t reproduce. The name comes from Chimpanzee Adenovirus Oxford 1 novel CoronaVirus-19… catchy name huh?! No wonder it’s known as the Oxford vaccine!
This is different to the Pfizer and Moderna vaccines which contain genetic material in the form of RNA which is then used by our own human cells to “make” the spike protein. Most vaccines in use are the normal “here’s a virus…the body recognises it as an invader and launches an immune response” technique, the Pfizer and Moderna vaccines use a “here’s the virus’s RNA blue print, let the body make the virus and spike protein itself, and then launch an immune response”. This RNA method is not so well known or used.
The Oxford vaccine stimulates an immune response by using the chimpanzee adenovirus to “present” the SARS CoV2 spike protein to the immune system. The immune system recognises that the spike protein associated with the chimp adenovirus is “foreign” and starts to produce both antibodies (from B lymphocytes) as well as active T lymphocytes against the spike protein. This should lead to the vaccinated person being immune to SARS CoV2.
Back in November 2020 the Oxford team published their phase 2/3 safety trial in the Lancet. In this study the ChAdOx1 vaccine was given to volunteers of different age groups (all over 18 years) and the recipients immune response to the vaccine was measured as well as any adverse events. The vaccine was shown to be very effective at triggering the production of antibodies as well as T cell mediated immune responses against the coronavirus spike protein. Local and systemic side effects to the vaccine after the 1st priming dose were more common in younger recipients; 88% 18-55 years, 61% in >70 years. The most common side effects were pain and tenderness at the injection site plus fatigue, headache and malaise. There were no serious adverse events caused by the vaccine.
Moving on to the Phase 3 trial
Last week, just as I was complaining that Pfizer hadn’t published any data about their vaccine, the Oxford Group published the interim results of their phase 3 ChAdOx1 study in The Lancet. This publication is really important and I commend the authors and AstraZeneca for getting their data out into the public arena to allow those of us who are expected to give advice on these vaccines to see what is going on.
The study took recruited volunteers between April and November this year, in the UK, Brazil and South Africa. This was a prudent choice of locations as it allowed, in an ethical way, for rates of Covid-19 exposure in vaccine recipients to fluctuate over time in one country whilst potentially staying high in another i.e. the study allowed for varying levels of Covid-19 whilst still carrying out an effective evaluation.
The interim analysis includes 11,636 of the total 23,848 participants; the remaining cases either have not had all their data gathered or are in the South African arm of the study which remains blinded, so the authors can’t include them as they don’t know which group these participants are in yet.
In the study, volunteers were given two doses of vaccine 28 days apart. So far recipients have been followed up monthly to an average of 3.4 months after the second dose. Just like with the Pfizer vaccine the study is only partially blinded; the administrator knows what vaccine they are giving but no one else does. Unlike the Pfizer study though the control for most participants is another vaccine (Meningococcal ACWY conjugate vaccine) to ensure that both study and control recipients can’t tell what they have received if they have no local reaction. Most vaccines give a localised reaction; in the Pfizer vaccine they used saline as the control, which will not produce a localised reaction. “Knowing” by either having a reaction or not having a reaction may change the participant’s behaviour e.g. they may partake in more risky behaviour if they think they have been vaccinated or less if they do not. Studies just want participants to go about their normal behaviour.
What was good?
I like the design of the Oxford study. It recruits volunteers from various countries and ethnic backgrounds, it looks at all ages of adults, and the variation in demographic details between ChAdOx1 and control groups is exceptionally well balanced i.e. both groups are comparable.
I also really like the use of another vaccine as the control to allow for local side effects in both arms (pun intended!) of the study. One suggestion that has been made is that the efficacy result may seem lower than Pfizer’s (70% vs. 95%) due to the use of this control vaccine. Interestingly (NB. ECIC has given permission for me to use the “I” word!) other studies around the World have observed that administration of routine vaccines seems to have “primed” the immune system and this priming has had the beneficial side effect of heightening the body’s alertness to new viruses and given some “protection” against SARS Cov2. If this is true the control group would have fewer Covid-19 cases too making the “difference” between vaccinated and control less dramatic. Pfizer’s control on the other hand was saline as a placebo.
I also like the way the results have been presented. There is a lot of gritty detail comparing doses of vaccine, age related efficacy and side effects, as well as adverse events (in the online supplementary material). It is really important that this type of detail is given to us all, not just the science by press release headlines we are getting from other pharmaceutical companies… we want warts (well not literally!) as well as the warm fluffy stuff PR companies are so good at producing.
Furthermore, I am impressed that AstraZeneca has promised 67% of the vaccine to developing countries at cost price (max $3 per dose). This is brilliant and shows the ethics of a company that is putting World health above profit. Well done AstraZeneca!
And another thing is the vaccine can be distributed using regular logistical means unlike Pfizer’s vaccine that needs to be kept at -70oC; the Oxford vaccine can be stored in a normal fridge for 6 months… and that is much more feasible in terms of World distribution.
What was not so good?
One glaring cock up in the trial had to do with the manufacturing of the vaccine. Due to an error in quantifying the amount of virus in the vaccine a proportion of volunteers in the UK arm of the study received a low primer dose of vaccine, about half of what they should have received. Whoops, I would have loved to be a fly on the wall when that was discovered! The error has though given one of the most intriguing results of the study in that the vaccine does appear from the interim analysis to be more effective at preventing Covid-19 when given as a low dose primer with a standard dose booster… weird! But wonderfully this is often how medicine makes “major progresses”, just think of Penicillium notatum landing on Fleming’s Staphylococcus aureus cultures! This may just be a quirk of the statistics in that the numbers of cases involved were small but it is a fascinating observation. However, if it really is the case (1/2 dose followed by full dose) I’m a little concerned as different doses for different stages of the vaccination program could potentially cause errors to occur…! “Was it the red bottle then the blue or the blue followed by the red?!?... Why didn’t they just label it 1 and 2?!
Another aspect of the study I find problematic is that they used different controls for different countries; most patients got the Meningococcal ACWY vaccine as the control, but some got a saline placebo. Other than showing a difference in local reaction which might indicate who had had the vaccine, I can’t really see how this would adversely affect the study results… I just find it disconcerting that they are pooling results from different study designs. I suspect it was done due to the meningococcal vaccine not being licensed or available in a country.
It may surprise you that some people who volunteer for studies choose to leave the study part way through, but it does happen. This occurred in this study too, some participants chose to leave having just had one dose of vaccine (either Meningococcal ACWY or ChAdOx1). However I would like to know why there were more participants in the ChAdOx1 group who chose not to receive the second dose of vaccine; if this was because of side-effects then it would be relevant and they should have been included in the side effect reporting. If there was another more innocent reason then please tell us.
My final problem isn’t specifically with the ChAdOx1 vaccine but with all of the Covid-19 vaccines. We do not have any long-term safety or efficacy data. The phase 3 ChAdOx1 trial has been recruiting since April so we do have some 6 month safety data (which is better than the 2 months we have for the Pfizer vaccine). But we still don’t have “proper” long-term data, and like the Pfizer study the Oxford study has also not finished yet. I am not aware that there has ever been a vaccine used before the clinical trial has ended… I know this is a global pandemic but….
I am a bit more confident with the ChAdOx1 vaccine design compared with the RNA vaccines though, as it is a standard “known” way of providing vaccines, so I would expect it to be safe, but no one knows how long the vaccine induced protection lasts; which is one of the points of the “length of a study”. At this point it’s anyone’s guess.
What do the results tell us?
Overall, the ChAdOx1 vaccine is 67.1% effective at preventing symptomatic Covid-19 infection. The authors quote 70.4% but that only includes patients with the 5 specific symptoms of Covid-19 they predefined at the start of the study (fever, cough, shortness of breath, loss of sense of smell or loss of taste) when you factor in all “known” symptoms the efficacy was 67.1%. This is still “good enough” to reduce transmission in the community even if it is not in the “ideal” 90% range. However it does mean more of the population need to be vaccinated to get an appropriate level of community protection.
The phase 2/3 study showed that the vaccine was just as effective in all ages over 18 years, and not just in the younger adults (figures 4, 5 and 6 in the paper). This is really important as we know that it is the older population most at risk of severe Covid-19 infection.
The vaccine appears to reduce the severity of disease even if it doesn’t prevent all infections. There were no hospitalisations or severe infections in the vaccine group compared to 6 cases in the control group. This may not sound like a lot but if you extrapolate to the current situation in the UK there could be 18,000 less Covid-19 patients in hospital (correct as of today) and then our NHS could be functioning normally – not bringing the health service to its knees with hospitalised patients is a major success of any vaccine!
Unfortunately the vaccine appears to reduce asymptomatic infections by only 7.8%, so asymptomatic transmission may still be possible between vaccinated and unvaccinated individuals. This is a shame as any vaccine that prevents transmission as well as the disease would be amazing… but in reality many current vaccines don’t actually achieve this, it is just too difficult to do. And a little greedy to ask for!
So, have I changed my mind about vaccines?
I’m really pleased that the Oxford Group have published their data. OK some look at the headline figure and say that it doesn’t sound as effective as the Pfizer and Moderna claims of 95% efficacy… but where is their proof. None of us have seen it! If the Pfizer and Moderna vaccines are so good, why haven’t hey published anything?
Personally, I would be much more likely to have a less effective vaccine that has been openly studied and scrutinised than a vaccine produced behind closed doors where I know nothing about the results.
The Oxford vaccine looks safe and effective at preventing Covid-19, and even better at preventing severe Covid-19. If I had a choice to have the Pfizer vaccine, the Moderna vaccine or the Oxford vaccine, then I can quite happily say I would have the Oxford vaccine. For me, it’s all about trust!
Conflicts of Interest
The ECIC and I once lived in an amazing little basement flat on the Woodstock Road in Oxford… but otherwise I have no link whatsoever with Oxford, AstraZeneca or anyone involved in producing any vaccine.
Have a look at the BBC’s Panorama program “The Race for a Vaccine” as well. This follows the researchers at Oxford during their “Covid-19 year”, I really do think it was a good documentary and gave a glimpse into a vaccine research lab.