The Oxford Saga: A New Hope

This post has been reviewed by Dr. Brett Finlay and Dr. Carolina Camargo, some of our subject matter experts.

The paper we’re demystifying today can be found here, if you’d like to follow along.

TL;DR:

The Gilbert group’s vaccine candidate, ChAdOx1 nCov-19, was found to be safe and well-tolerated in the group of patients that was tested. This group consisted of young, healthy people and most study participants were white- based on this, further trials are needed in older age groups and more diverse populations. The side effects of the vaccine were mild to moderate and can be managed with Tylenol. Using Tylenol did not affect the immune response to the vaccine. In a small trial, a booster dose of vaccine seems to increase antibody levels. One of the most attractive things about this vaccine is that it’s causing an immune response at both the antibody and cellular level. Phase 3 trials are currently taking place in Brazil, South Africa and the UK.

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Research groups across the world are working on a variety of vaccine types against SARS-CoV-2, including mRNA and DNA based, adenovirus and whole killed vaccines. Most of the vaccine candidates against SARS-CoV-2 are designed to target the spike protein of the virus.

By the time this post goes up, the new big news would have already made the rounds: the phase 1/2 data from the famous Oxford University-lead vaccine effort has been released. ChAdOx1 nCoV-19 is a live attenuated adenovirus that’s been modified to express the SARS-CoV-2 spike protein, and it’s been stirring up a lot of excitement. Dr Sarah Gilbert, the researcher in charge of the group working this vaccine, has been featured in articles like this one by Bloomberg. The entire world has been watching this particular trial with bated breath, and now here it is.

So let’s get to it.

Introduction

At the current time, there are more than 137 SARS-CoV-2 vaccine candidates in pre-clinical development. Of those, 23 are in early clinical development¹. In the introduction of this paper, the authors also outline the qualities of an ideal SARS-COV-2 vaccine candidate. It would have to do the following:

• Work after 1-2 doses
• Protect populations who are at higher risk, including older adults and people with other pre-existing health conditions
  • This includes safely protecting people with compromised immune systems or autoimmune diseases
• An ideal vaccine would have to give at least 6 months of protection after the initial vaccination
• Vaccinated people should not spread the virus to other people as easily.

Enter the ChAdOX1 vaccine. “ChADOx1” is a name for a class of vaccines, all using the same vector- a replication-deficient chimpanzee adenovirus. Now, what does all of that mean? To break it down:

There is evidence of replication-deficient viral vectored vaccines being used safely in people with compromised immune systems². Other ChAdOx1 vaccines have also been used in older adults and caused a strong immune response. ChAdOx1 type vaccines can be made very quickly and at a large scale.

Professor Gilbert’s group is particularly well suited to this experiment because of some of their past work. This group was working on a ChAdOx1 based vaccine for MERS (Middle East Respiratory Syndrome). In their past experiments done on monkeys, the group showed that a single dose of their MERS vaccine could protect monkeys from MERS-CoV. They built on this work to make the vaccine we’re discussing today- a ChAdOx1 vaccine expressing a sequence for the SARS-CoV-2 spike protein. When the researchers tested their vaccine in rhesus macaques (a type of monkey), they found that a single dose of the vaccine causes both humoral and cellular immune responses.

What does that mean? Well for an immune system review you can’t do much better than Deanna’s sidebar series. As a quick recap- antibodies are the bread and butter of the humoral immune response. Antibodies can act as a bullseye for T cells to latch on to, which targets the immune system to the virus. Also, some (but not all) antibodies are neutralizing antibodies. Neutralizing antibodies are very important in the immune response. They can surround the virus and prevent it from infecting cells. A ‘humoral immune response’ means that your B cells are producing these antibodies. A cellular immune response means that the T cells in your body are waking up and setting out on the hunt. This ‘awakening’ of T cells happens during the natural infection process. If a vaccine can stimulate it, that is very good news.

In other words, monkey experiments showed that this vaccine is ringing all the alarm bells- it’s providing two layers of protection against the virus. After the success of the animal trials, the researchers moved to human tests. For this, they did what’s called a single-blind, randomised controlled trial. As their control, they used a meningococcal vaccine, currently licensed for and used in humans.

Methods

The methods section of this paper is very long, so I’m going to try to give you the main highlights.

This study was conducted at five different centres. As I said above, it was single-blinded (aka, participant-blinded), so the study participants didn’t know whether they were getting the ChADOx1 nCoV-19 vaccine or the control meningococcal vaccine. All the participants were healthy adults aged 18-55. They went through a pre-screen where they were evaluated for basic medical history (HIV, Hep B, liver/kidney function, etc).  Any patients who had potentially been exposed to SARS-CoV-2 or who showed symptoms of the virus  were excluded from the study.

These participants were randomly assigned to either the ‘experimental’ (ChAdOx1 nCoV-19 vaccine) group or the ‘control’ meningococcal vaccine group.

The volunteers in this study were broken up into four groups:

• Group 1: Group 1 acted as the phase 1 part of this study. These volunteers had in-depth follow-up visits early in the trial to ensure safety and regular follow-ups thereafter (days 3, 7, 14, 28, 56)
• Group 2 -> The participants in group 2 had larger blood samples taken and those blood samples were used for both humoral (antibody-based) and cellular (T-cell based) immune response tests
• Group 3 -> the researchers call this the ‘prime-boost’ group. Group 3 had only 10 patients in it. These patients were not blinded; all members of group 3 received the experimental COVID19 vaccine and were aware of that. These patients, unlike those in other groups, actually got 2 doses of the vaccine- an initial priming dose and then a booster 28 days later. These patients were followed closely for both safety and immune testing purposes.
• Group 4 -> these patients had a lower blood volume taken than group 2 and were only tested for humoral immunity.

At 2 of the 5 study sites, patients were told to take paracetamol (Tylenol) after the vaccination, every 6 hours for 24 hours. Patients taking Tylenol were evenly randomized to either the trial or control categories.

Patients were watched in the clinic for 30-60 minutes after vaccination and were also asked to report any side effects using a journal for the next 28 days. The severity of reported side effects was categorized as mild, moderate, severe or life-threatening. These categories were defined as:

• Mild side effects would cause short-lived, low level discomfort that went away within 48 hours without requiring medical treatment
• Moderate side effects might have caused a slight limitation in activity but did not require medical treatment
• Severe side effects cause a big limitation in activity and require medical treatment
  • Note: no serious side effects were seen in the vaccine trial
• Life-threatening side effects are those that require hospitalization or assessment in an emergency room
  • Note: no life-threatening side effects were seen in the vaccine trial

Two independent doctors also classified the side effects by the likelihood of them being caused by the vaccine- these doctors were not told which vaccine the patient was given.

All patients had blood samples taken at days 0 and 28. The samples were analyzed for a T cell response using a very specific, special assay. Humoral responses were analyzed before and after vaccination using an enormous battery of assays.  The researchers also acquired plasma samples from adults who tested positive for SARS-CoV-2 and ran those samples in some assays as a comparison.

Results

Overall, this study involved 1077 participants. Of those, 534 were given the experimental vaccine and 534 received the placebo. Of the patients that were given the experimental vaccine, 10 got the prime-boost dose (2 doses, 28 days apart).

The study also used plasma samples from adult patients who tested positive for SARS-CoV-2 and ran these plasma samples in some of the same tests. This was used to find a baseline. This was also used to see how the immune response caused by their vaccine compares to an immune response caused by a natural infection.

Immune responses

For the patients who received the trial vaccine, antibodies against the spike protein of SARS-CoV-2 reached a peak 28 days after vaccination. These levels stayed high up to day 56. In the prime-boost (two doses) patients, the highest antibody level was on day 56. These results were confirmed by data collected using a different assay. There was no difference in generated immune response between the patients who took Tylenol and those that didn’t.

(One type of assay the researchers used is a viral plaque assay. They also used ELISAs. Click the links to check out our sidebars explaining how those assays work!)

All of the tested participants had neutralizing antibodies at day 28. Importantly, this was confirmed by several different assays and techniques. This is really important because it shows that the results are real, not just a result of a particular technique or assay. The researchers found that some patients had neutralizing antibodies that were able to prevent the cytopathic effect of SARS-CoV-2. The cytopathic effect is a name used for the physical changes a virus makes to its host cell, such as breaking the cell open, fusing with neighboring cells, or rounding of the infected cell (Agol, 2012. Cell).

62% of the patients had neutralizing antibodies that completely prevented the cytopathic effect of SARS-CoV-2.  Of these, 100% of the patients in the prime-boost group produced these cytopathic effect-fighting antibodies.

As far as humoral immunity goes, this is all good news. When comparing the humoral response to the vaccine with the response to natural exposure to the virus (someone coughing on you), the researchers found that the vaccine causes a similar level of immune response.

When testing for a T cell response, researchers found that their vaccine causes an increase in spike-specific effector T-cell responses. This increase on day 14 and dropped by day 56 post-vaccination.  

Side Effects

The most common side effects of the ChAdOx1 nCoV-19 vaccine were fatigue and headaches. Other common side effects were muscle ache, feeling feverish and general discomfort. The side effects were usually the most present the day after receiving the vaccination but were overall mild to moderate in severity (classified as not needing medical help). Patients who used Tylenol for the day after vaccination showed a decrease in the severity of their side effects, including pain, feverishness, chills, muscle ache and malaise. Since Tylenol use doesn’t appear to affect the immune response to the vaccine, this is great news!

Discussion

Overall, it seems that a single dose of the ChAdOx1 vaccine was both safe and tolerated in the groups tested. The trial vaccine appeared to have a slightly higher chance of causing side effects than the trial meningococcal vaccine. However, the side effects seem to be mild to moderate and go away on their own. The side effects were easily manageable with Tylenol!

The researchers found that a single dose of their vaccine causes an increase in spike-specific antibodies by day 28 post-vaccination. After a booster vaccine, all participants had neutralising antibodies.

In primate studies, similar antibody levels were enough to protect against SARS-CoV-2 infection. We’ll have to see if that extends to the human study as experiments continue.

The researchers also found that their vaccine causes an increase in SARS-CoV-2 spike-specific effector T cell response, only 7 days after vaccination! This response peaked at day 14 and extended out to day 56 post-vaccination. Giving a booster shot did not increase the T-cell response, which wasn’t surprising given the data out there. Importantly, we have keep in mind that only 10 patients received this booster shot. This means that the data on the booster vaccine isn’t definitive- we need more trials to be absolutely sure.

Important to note- when the researchers say that the antibodies extended to day 56 post vaccination, that doesn’t mean the antibodies went away after that! It just means that day 56 is the furthest this particular data set went. The study is still ongoing so we’ll be seeing some longer-term measurements in a little while.

Since SARS-CoV-2 hits older adults worse, any potential vaccine must be safe for older age groups. ChAdOx-1 based vaccines against influenza have been used safely in older adults. Other studies have reported low anti-vector immunity. This means that the body’s immune response to the vector used in the vaccine was low in comparison to the immune response to the SARS-CoV-2 spike protein.

The researchers in this study want to do further experiments to see whether anti-vector immunity might make it difficult to give booster shots. That being said, their existing data has shown that a booster shot can be given and is still effective.

Limitations

These researchers aren’t shy about the limitations of the study. They list known limitations as:

• Short follow-up reported. The patients were only watched for 56 days after the vaccination, although since the study is still ongoing this follow up will be extended
• A small number of participants in the prime-boost group. Only 10 patients received the two doses of the vaccine
• Single-blinded design. A double or even triple-blinded study design would eliminate many more potential sources of bias.

Another limitation of the study is that the findings might not apply to all members of the world population. Most of the study participants were white, and all were young and healthy. For this data to be applied to everyone, the study will have to be extended to people of diverse ethical backgrounds, people with pre-existing conditions and older age groups. The researchers plan to conduct such a study, with a follow-up time of 1 year. Also, more research is required to check whether the protection given by this vaccine is extended to that critical 6 month goalpost.

Conclusions

Overall, ChAdOx1 nCov-19 was found to be safe and well-tolerated in the group of patients that was tested. That being said, it’s important to remember that this group consisted of young, healthy people and that most study participants were white. The side effects of the vaccine were mild to moderate and can be managed with Tylenol. Using a booster vaccine seems to increase antibody levels, but the number of study participants who received the booster was small. One of the most attractive things about this vaccine is that it’s causing an immune response at both the antibody and cellular level. This data is promising and has supported the researchers into extending the study into phase 2 and 3 trials. Phase 3 trials are currently taking place in Brazil, South Africa and the UK and there are plans to test the virus in people from diverse backgrounds.

As exciting as all of this seems, we have to remember that we don’t know whether the vaccine works yet. We know that it’s safe (in the groups it was tested in) and vaccination seems to cause production of neutralizing antibodies. Whether that leads to protection against infection, and how much protection it gives, is something we’ll have to find out in future trials. That being said, things certainly look promising.

It’s been a long ride since the start of the pandemic, and we’re not quite out of the woods yet. But there’s a light at the end of the tunnel now- and it seems like everything’s coming up Chad.

References:

1. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. Fidler S, Stöhr W, Pace M, et al. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet. 2020;395(10227):888-898. doi:10.1016/S0140-6736(19)32990-3