“Oxford vaccine causes double defence against COVID-19” was the overnight breaking news in the Telegraph. Rather unusually there has been an unofficial leak from a “senior source” concerning the initial results of the Oxford Vaccine study. Astra-Zeneca shares have soared even though they are in a non-profit arrangement with Oxford University over this vaccine. Of course I am not in a position to confirm or deny this leak. But it would not surprise me if we hear that it is indeed true.

UPDATE 20 July 2020 The Oxford results are now officially released. Paper here as well as a second similar publication from a similar vaccine in China: oxford paper https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620316044.pdf commentary https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620316111.pdf

This all comes hot on the heals of a report that the Moderna vaccine also produces antibodies in humans. As I outlined in a previous post the Morderna vaccine is an RNA vaccine. The Oxford one simply envelopes RNA in a non-replicating cold virus, protecting it and delivering it direct to human cells. If the Moderna vaccine works, then you could reasonably expect the Oxford vaccine might perhaps be at least as good.

What the Telegraph is reporting is that the Oxford vaccine has been shown to produce not just antibodies but a T-cell based immune response. This is crucial because T cells are critical in our response to viruses, and also play a part in immune memory. There has been concerns, which I will outline below, about whether or not antibody levels would remain high after either an infection or an immunisation. If T-cells are also being affected by the vaccine then this might indicate the possibility that the vaccine could have a long term protective effect.

It is just conceivable that authorities might even decide to proceed with wide-spread vaccination on the basis of these initial results, but more likely they will wait for more robust data. The hope is still that we may be able to vaccinate millions from September when the huge numbers of doses being produced “at risk” will be ready.

We do not yet know whether this vaccine actually protects humans from COVID-19 infection or reduces the severity of an infection if it occurs.

The following article, the next in a series, was already almost ready to be published. It relies on the previous posts in the Corona Hope series, particularly “How vaccines work” and “A plug and play vaccine platform”

We will look today at the Oxford vaccine in more detail, discussing this potential huge turning point in modern medicine. If this vaccine works not only will it make a huge impact on the coronacrunch, it could be a huge turning point. The assumption is that the Oxford plug and play vaccine platform could be used to make vaccines for anything, including protein markers found on cancer cells. Some of the information that follows was found in this article which will be updated with news as it develops.

The goal of the Oxford vaccine is to turn a few of our own human cells into little vaccine factories. It’s a plug and play platform allowing us to identify any protein that we think we need to produce antibodies against and insert the corresponding RNA for that protein into one of these chimpanzee common cold viruses. The injected virus has been modified so that it cannot multiply and cause disease in the human body. Therefore it is called a non-replicating viral vector. The protein fragment produced is small enough that it cannot cause disease.

The reason for using a chimpanzee virus this is because we do not have antibodies to the delivery virus, whereas if we were going to use a human cold virus our immune systems would prevent it delivering its payload.

“It’s safe because it can’t replicate, it can’t spread through the body after infection so even if somebody’s not able to make an immune response because they’re very severely immunocompromised for example this would not be a dangerous vaccine to give them. It’s not going to cause an infection that would cause them any harm, but it does induce very strong immune responses that when we use it as a vaccine”

Sarah Gilbert, head of the Oxford COVID19 vaccine program
https://www.youtube.com/watch?v=MKNavonhXyk

Experts believe that the Oxford vaccine will not be dangerous for immuno-compromised patients, which would include blood cancer patients.

The Blood Cancer UK review of the Oxford vaccine concurs with the idea this is not a “live vaccine” in the way we think of them typically and so should be safe for blood cancer patients to take, although of course we do not yet know if they will respond well to it.

The Covid19 vaccine trial participant information sheet shows that immune compromised people are not going to be allowed to enter the current study. This seems to be because of concerns about whether the vaccine will work rather than it potentially being dangerous for those with poorly functioning immune systems.

Background to the Plug and Play Platform

Over 6000 patients had taken one of the vaccines based on this model in twelve different clinical trials  prior to April 2020. Examples include TB, flu, AIDS, chikungunya, MERS (another coronavirus), and prostate cancer. The safety profile was is well known and as you would predict from any normal vaccine. There were no surprises.  

Perhaps early on we should mention one unknown factor that may influence the success of any COVID-19 vaccination program which is one reason why the report that T-cells being affected may be so crucial.

Human diseases vary hugely in how strong and enduring an immune response they produce. Some diseases like the common cold often only produce mild antibody response that is short lived, and so reinfections can happen even after only six months. Other diseases we contract as children produce an immune response that lasts for decades.

A recent paper examined stored blood from a limited number of patients concerning infections with previous coronaviruses that have circulated in the population. These only cause the common cold, however, and are very different to COVID19, MERS and SARS which all often cause much more severe illness.

There is a group of coronaviruses that have been infecting humans for a very long time. They are one of the causes of the common cold. A recent small study looked back at stored plasma from years ago for evidence of how antibodies to these coronaviruses performed.

“The majority of patients lost 50% of their NCt-protein-antibodies after 6 months, 75% after a year, and completely returned to baseline 4 years post-infection”

https://www.medrxiv.org/content/10.1101/2020.05.11.20086439v2.full.pdf

We might conclude from this that people will be susceptible to reinfection with COVID19 from as soon as six months post their infection, and similarly that any vaccine would only protect them for a short period of time. However, two factors suggest this might not be the case:

1. The lack of reliable evidence so far of widespread reinfection not just with COVID19 but with MERS and SARS. MERS and SARS are much more like COVID19 than the older coronaviruses.
2. More severe infections with any disease tend to be associated with a longer duration of immunity.

We are only just beginning to be able to reliably track antibody production to COVID-19. Recently one small study concluded that there was a lot of variability in the strength of the immune response seen to COVID-19. Those with mild illness produced less antibodies than those with more severe illness. The study also demonstrated the reduction in the acute antibody response you would expect, alongside evidence of a “memory” response appearing. This suggests that at least some people might have ongoing immunity to COVID-19 but doesn’t answer the question of for how long.

There seems to be an emerging belief that if COVID-19 antibodies are present in the blood we might hope they are protective.

But if it is true that antibodies against COVID-19 either prevent infection or reduce its severity, we will still need to track patients after both infection and vaccination to see just how long those antibodies last.

We may have to vaccinate many people more than once, but right now we simply do not know. This uncertainty is why at the moment health authorities are warning us that we do not know if testing positive for the antibody is a guarantee that you are immune from infection. And even if it was, we cannot tell how long someome would remain immune at this point. Similar warnings will no doubt be in place even if we discover a working vaccine.

At some point we may well be able to confirm with more evidence that it is unlikely for someone to get a severe COVID19 infection if they have antibodies in their blood. That is certainly the hope behind all vaccination efforts. And as we shall see there is animal evidence supporting that. But right now we do yet even know this for certain. But I do think there is good reason to hope that is the case.

It is certainly also possible that having had COVID19 or a vaccine might prevent you from getting the life-threatening pneumonia but could turn COVID19 into a mild cold-like illness affecting just the throat and nose. That could of course be an issue for those of us with poor immunity. If we are not ourselves able to respond to the vaccine someone infected with a throat based version of the disease might not feel very unwell but might conceivably still be able to infect unprotected people. This is probably one of the concerns of the health authorities at the moment and why they are stressing that we do not fully yet understand the significance of antibody test results. As we say all too often during this epidemic, time will tell.

There is much we do not know about how COVID19 effects the immune system. So for example we understand that T cells are also involved in the response but somewhat surprisingly the most severely ill patients seem to be seeing a destruction of their T cells. Since blood cancer patients can have poorly functioning T cells this might also be part of the reason we are at higher risk.

There is evidence antibodies protect against COVID19 infection in monkeys

Peer reviewed research in monkeys have recently been published which shows encouragingly that prior exposure to COVID19 does lead to producing antibodies, and that those antibodies prevent subsequent reinfection.

Results of the Oxford vaccine in monkeys follow below. Another study in monkeys has also been published following peer review and shown that certain DNA vaccines can produce protective antibodies which make them immune to subsequent infection.

But lets get back to the specific case of the Oxford vaccine. We do know that an earlier version of the plug and play vaccine can prompt the production of antibodies to the MERS coronavirus which is in some ways very similar to COVID19.

MERS Oxford Vaccine Candidate Phase I results

The graph below demonstrates a good immune response to the Oxford vaccine candidate for MERS. Antibodies clearly are produced. The results were best with the highest dose so this allowed them to assume that this would be the best dose for the COVID19 version also.

The vaccine was immunogenic at all doses, inducing seroconversion in the majority of participants and T-cell responses in all, with responses demonstrating good durability up to 1 year after vaccination. Onset of detectable immune responses was rapid, with T-cell responses peaking 14 days after vaccination and antibodies at 28 days.

Lancet: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172901/

SARS is another earlier coronavirus which causes severe illness in humans. Some vaccine candidates for this disease (not from the Oxford group) led to a worse infection in animals who were vaccinated than those who were not. Somehow the vaccine was stimulating the excesive reaction which causes the lung inflammation. Eosinophils were seen infiltrating the lungs. This was due to the production of non -neutralising antibodies which made it easier for the disease to enter cells. This phenomena is called “Vaccine mediated enhanced disease” It is essentially the wrong type of immune response being produced. Fortunately it is possible to test for this in animals.

In the early animal studies of the Oxford vaccine for COVID19 the wrong kind immune response was not seen. They vaccinated mice early in the year. The correct sort of neutralising antibodies were caused in the mice. All indications were that the right sort of response was happening. The results of this study are discussed in the above video. Since mice are not susceptible to COVID-19 they turned to a species more similar to humans for a crucial study.

Non human primates (monkeys) were vaccinated with the Oxford vaccine and then given a very high dose of Covid19 (direct to trachea, eyes, nose and throat).

Vaccinated monkeys did not develop COVID-19 pneumonia.

There was no viral replication in the lungs of any of the vaccinated monkeys. There was some viral replication in the nose but this was only short lived. The conclusion was that the vaccine was preventing pneumonia which is what is killing most people with COVID19. Perhaps we could say that the vaccine converted the illness in monkeys to a common cold.

But the amount of virus given to the vaccinated monkeys was so severe that with a more normal amount of exposure they might not even have experienced the mild nasal infection. The real question of course is what will happen in humans. But here is a summary of the results in more scientific speak:

“A single vaccination with ChAdOx1 nCoV-19 induced a humoral and 26 cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed.”

https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1.full.pdf

Phase I Study of COVID19 (April 2020)

The first large clinical trial for the Oxford Vaccine has already been recruited and other even larger studies are ongoing or about to start. The first set of results of this study was always going to be what the effect on antibodies and T cells are.

The patients will have to be followed for longer to see if more COVID-19 infections happen in the control group than the vaccine group. Ironically the reduction in infection rate in the UK may mean these studies take longer to have enough infections to give a clear answer. As a result other studies are also being started in high risk areas including the USA and Brazil.

There is another UK Phase 3 trial which includes 10,000 people. It is prioritising health care workers due to their higher risk and therefore greater chance to potentially benefit.

So far 8,000 volunteers have been recruited into the Oxford Vaccine trials.

We now potentially have at our fingertips a limitless tool. We don’t have to spend years developing a new vaccine we can simply plug and play the target protein’s code into this delivery tool. Ever since the development of the monoclonal antibody Rituximab doctors have been looking for ways to turn our own immune system against cancer.  In the future perhaps we will be able to take a vaccination against some cancers, including potentially blood cancer.  

AstraZeneca has already made plans to manufacture 2 billion vaccine doses on a not for profit basis.

That’s really all we can say at the moment about the science. There is a good reason to believe that this vaccine and others might actually work against COVID-19. Let’s hope so.

For some blood cancer patients it is possible that vaccines may not produce the antibody response we are looking for. But other options are being studied. which are more likely to work for us, including convalescent plasma, IVIG, and even monocloncal antibodies.

Timeline of key developments

The Oxford vaccine is a real story of partnership. Almost seen as a niche interest before this epidemic the plug and play platform was undergoing a slow typical development. It was almost a tool waiting for a major need that it could address.

With support from the UK governement made avaialble early on during the epidemic, there has since followed a non-profit deal with a major pharmaceutical company, Astra-Zeneca. And coupled with further investment from both the UK and USA governments huge volumes of the vaccine are being produced as we speak with the goal of being in a position to start vaccination in both countries as soon as September if the data supports it.

There are also deals going through in other countries including a clear committment to make this vaccine readily available in developing countries who might not otherwise be able to afford it.

January 2020 Genetic code of virus released. Oxford university are almost immediately able to manufacture a vacine candidate using their plug and play platform of a non-replicating virus vector.

30 April Astra Zeneca and Oxford University joint press release days after the first human doses were given lists the following key points:

• AZ will now oversee global development, manufacturing, and distribution of the “Oxford vaccine”
• The single-blinded, randomized clinical trial was by then already underway in five centers in Southern England.
• The Phase I clincal trial is described on clinical trials.gov

“Our hope is that, by joining forces, we can accelerate the globalization of a vaccine to combat the virus and protect people from the deadliest pandemic in a generation,”

AstraZeneca CEO Pascal Soriot https://www.genengnews.com/news/astrazeneca-joins-u-of-oxford-and-spinout-to-develop-covid-19-vaccine/

May 18, 2020 – The partners to the statement a month previously finalised a financial an agreement with the UK government with the Imperial College London and AstraZeneca to produce at risk the ChAdOx1 nCoV-19 vaccine.  This made the UK the first government in the world to effectively purchase doses of this vaccine for its own population before we even know if it works. 30 million doses were to be produced by September with 70 million more to follow for the UK. Already AZ stated they were “in talks with governments around the world to strike coronovirus vaccine production deals similar to one it agreed with Britain over the weekend.” Oxford University stipulated that one condition of their partnership was that this would be rolled out to every country that needs it and at prices that are affordable for the worlds poor.

“A Phase I/II clinical trial of AZD1222 began last month to assess safety, immunogenicity and efficacy in over 1,000 healthy volunteers aged 18 to 55 years across several trial centres in southern England. Data from the trial is expected shortly which, if positive, would lead to late-stage trials in a number of countries. AstraZeneca recognises that the vaccine may not work but is committed to progressing the clinical program with speed and scaling up manufacturing at risk.” [emphasis added]

https://www.astrazeneca.com/media-centre/articles/2020/astrazeneca-advances-response-to-global-covid-19-challenge-as-it-receives-first-commitments-for-oxfords-potential-new-vaccine.html

May 21, 2020 $1 Billion investment from the USA government to develop the vaccine further and supply the USA initially with at least 400 million doses of the vaccine.

June 9, 2020 Deal with Indian vaccine manufacturer to initially produce 1 billion doses for India and low to middle-income countries.

June 13, 2020 Deal signed to supply 400 million doses to mainland Europe starting at the end of 2020.

June 28, 2020 Brazil deal concludes enabling it to make 100 million doses of the vaccine in country, and confirming a large clinical study is happening there.

14 July 2020 Major CRO IQVIA announces it is partnering Astra-Zeneca to deliver the huge USA study of the Oxford virus.

Read More

• Precision vaccines update
• BBC News: “Can you get Coronavirus twice?”
• Interview withh Dr Fauci’s boss
• Telegraph overview
• Blood Cancer UK overview