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The COVID-19 vaccine – where are we at?

Sammi:
 
Good evening everybody and welcome to this evening’s webinar, The COVID-19 vaccine – where are we at? We are joined by our presenters this evening, Professor Kristine Macartney and Dr Ketaki Sharma. Before we jump in, I would like to make an Acknowledgement of Country. We recognise the traditional custodians of the land and sea on which we live and work, and we pay our respects to Elders past and present.
 
I would like to formally introduce our presenters for this evening now. Professor Kristine Macartney is a paediatrician specialising in infectious diseases and vaccinology. She is a medical graduate of the University of New South Wales and undertook her specialty training in Sydney and in the United States at the Children’s Hospital of Philadelphia. Kristine is currently the Director of the National Centre for Immunisation Research and Surveillance, a Paediatric Infectious Disease Consultant at the Children’s Hospital at Westmead and a Professor in the discipline of Paediatrics and Child Health at the University of Sydney.
 
We are also joined by Dr Ketaki Sharm. Ketaki is a general paediatrician and a Staff Specialist at the National Centre for Immunisation Research and Surveillance. She is part of the New South Wales Immunisation Specialist Service and reviews children who have experienced an adverse event following immunisation. She is also currently undertaking a PhD focused on optimisation of antenatal vaccinations.
 
So thank you for joining us, Kristine and Ketaki.
 
Before I hand over to Kristine to get us started tonight, I would just like to take you all through our learning outcomes quickly. So by the end of this online CPD activity, you should be able to be aware of the potential COVID-19 vaccines that are currently under development and the progress of human trials, discuss vaccine platforms and development, be aware of considerations for vaccine prioritisation and allocation and discuss the safety and efficacy of the pandemic vaccine and the associated monitoring processes. So I will hand over to you now Kristine to get us started.
 
 
Kristine:
 
Wonderful. Thank you so much, Sammi and welcome everyone and thank you so much for having both Ket Sharma and myself, we are honoured to be here. I too would like to acknowledge the traditional owners of the land on which we are meeting and acknowledge Elders past, emerging and any Aboriginal and Torres Strait Islander people that are joining us today. As Sammi mentioned, we are going to discuss a number of the COVID-19 vaccine platforms and talk a little bit about the different technologies, focusing on some of the leading candidate vaccines, talk about immunogenicity and efficacy assessment, touch on implementation and prioritisation groups for vaccination, talk about safety assessment and monitoring and a little bit about time frames and next steps. And I put my next steps there because I know that at this time we all have things to think about as we get ready for what 2021 will bring with a COVID-19 vaccine or vaccines.
 
So I am going to now hand over to Ket, and I think she will be able to take control of the screen now and take you through some of the vaccines.
 
 
Ketaki:
 
Thanks, Kristine. So hopefully that works. There we go. So, I will dive right in. So to start off with, I am just going to give you an overview and then we will go in depth into each of the platform technologies that are currently being used. So just a big picture. There are sort of two groups of platform technologies. You can either make a vaccine where you are delivering the antigen directly in the vaccine, and so that is the group on the left where you can have a whole virus vaccine either live attenuated or inactivated, and everyone would be familiar with those. Or protein based vaccines, where you are delivering the actual protein in the vaccine. Then on the right-hand side there are the newer technologies which are delivering not the actual antigen itself, but the gene for the antigen. And that gene is in the vaccine, gets into the host cell via one of these mechanisms, and your host cell uses its own machinery to then manufacture that antigen and that triggers the immune response. So, we have many vaccines made with whole virus and protein technologies, and one of the benefits of the whole virus technology is that they will have multiple antigens because all of the proteins are present. At the same time it also means that there are other potentially more reactogenic compounds still present. Then the benefit of the protein viral vector and nucleic acid technologies is that they can all be made without actually having your hands on the virus itself. So what that means is, when the genome for SARS-CoV-2 was released in January, researchers were able to already start developing these three types of vaccines.
 
So protein based vaccines are made often using recombinant technology as well. You take the code for a particular antigen and manufacture it in another organism such as a bacterium. And then viral vector vaccines use a vector, so a carrier virus which is a harmless, unrelated virus such as adenovirus to carry the gene of interest. And the nucleic acid vaccines are either RNA or DNA and I will go into a little bit more detail of how they actually get the gene into the host cell. So, viral vector vaccines, there are actually two versions of Ebola vaccine that use viral vectors and it is also a technology that has been used for some years in gene technology. Nucleic acid vaccines, although they have been under development for decades, there are currently no licensed and DNA or RNA vaccines for use in humans.
 
So now having a look at the actual SARS-CoV-2 virus, what the actual antigens that you might use? You can see around the border of this diagram, the orange spikes. So that is the spike protein and so you would have seen that represented everywhere in the media. That is a protein that contains the receptor binding domain that actually attaches to the ACE2 receptor. And this is by far the most common antigen of choice in all the candidate vaccines, and this is supported by the research that was done into the original SARS virus, SARS-CoV-1 and that it was a protective target in vaccines. So what the vaccines might look like would be, you can see here the orange option of having the entire S protein as the antigen. Some vaccines might only have the receptor binding domain fragment. Then inactivated vaccines would have the whole virus but it would not be able to replicate. Live attenuated vaccines would have the whole virus and it would be able to propagate, and so these ones would have the additional antigens you can see that are surrounding them, so envelope protein, nuclear protein and matrix protein. And then the vector vaccines here use another virus to carry the gene for the spike protein inside, and the DNA vaccine uses a plasma to carry the gene for the spike protein and the RNA vaccine here I will talk a little bit more about it, it is encapsulated and has the mRNA inside.
 
So looking closely at the mRNA vaccines, these are very topical right now because they are the ones that you would have seen in the news, some recent announcements by Moderna and Pfizer which we will talk about later. So, what an mRNA vaccine is, is a piece of mRNA that is hard to get into the cell, because RNA gets broken down very easily by circulating ribonucleases and it is inherently very prone to degradation. So, what they have done is they have encapsulated in these lipid nanoparticles that helps it be protected against degradation and also helps it to enter the host cells. So with these are RNA and even DNA, they can be taken up when you inject it by myocytes but in particular if they are taken up by antigen presenting cells, that is when you are likely to trigger an immune response. So some of the benefits of the mRNA and DNA vaccines are that they are relatively cheap and easy to produce. As I mentioned, you do not actually need to have access to the virus itself, so you do not need sort of special biosafety level three facilities and they can be scaled up very easily, so you can potentially make hundreds of millions of doses within a few months or years. And the design is quite easy. Some of the issues are that they are not established technologies, so there are questions about the efficacy and they are as I mentioned prone to degradation. So you might have seen again in the media that these vaccines need very cold storage so the Pfizer candidate is currently recommended to be stored at minus 70°. That might change as they continue to do more stability testing or they might even reformulate it down the track. And the Moderna vaccine is a little bit easier to store, currently recommended at minus 20°, and then stable in the fridge for about 30 days. The other issue is that booster doses are likely to be necessary with this technology.
 
So having a look at the Pfizer BNT162b2. This is the result from the phase 1-2 studies, so not the phase 3 study, the interim analysis that was recently in the news. And having a look, you can see here on the right-hand side, this is the antibody levels in convalescent serum, so from patients who have recovered from COVID-19 infection. And then you can see there the blue columns are the current vaccine candidate that has been selected in adults aged 18 to 55, and then older adults aged 65 to 85, and looking at spike protein binding antibodies on the top and neutralising antibodies on the bottom. And basically the graph is just here to show you that it did induce antibody levels that were comparable to those of people who have recovered from COVID-19 infection. And then we have the announcement on the 9th November that they have done an interim analysis of their phase 3 study, and reported more than 90% efficacy. So that is a very exciting announcement, a great milestone and Kristine will be talking about that later.
 
So the next mRNA candidate that has been in the news is the Moderna vaccine. So that is also an mRNA vaccine that is encapsulated and encodes for the full spike protein and similarly, you can see here compared to convalescent serum on the right-hand side, it was immunogenic and it induced antibody levels that were comparable. And again, so they have had an announcement just two days ago that their first interim analysis showed greater than 94% efficacy.
 
So now looking at DNA vaccines. So these vaccines incorporate the DNA. It can either be naked or incorporated into a plasma, but it is very hard, it is not easily taken up by cells once it is injected. So the DNA vaccines have a couple of other options for delivery that are quite unique. One is this device here called an electroporation device. And so what that does, is it delivers in milliseconds electrical signals that create little pores in the host cells to facilitate uptake of the vaccine. So, some of the benefits of this technology is that it is again easier to design. It is rapid to manufacture and scale up. They are quite stable so the candidate vaccines produced by Inovio and there is another one, Synvivo can be stored at room temperature and the Synvivo which is a phase 1 candidate is actually an oral formulation like a probiotic. So, those are some of the benefits. Some of the issues are as mentioned, you might need special administration systems, adjuvants and there are potential safety issues because the DNA will obviously be taken up into the nucleus and there are currently no licensed DNA vaccines in humans, so we have limited experience with that platform.
 
Viral vector vaccines are either replicating or non-replicating. So these are the technologies that use a carrier virus, so common ones include adenovirus and they incorporate the gene or the spike protein into the carrier virus. The replicating ones can then propagate to a degree, so it sort of more along the lines of a live attenuated vaccine, and then the non-replicating viral vector vaccines cannot. So the benefits of this is that they induce very good humoral and cellular immune responses, and it is a proven technology in gene therapy. And as I mentioned, there are actually a couple of licensed viral vector vaccines for Ebola. But a couple of limitations include that it is more complex to develop and to scale up. And that it is possible that you could have pre-existing immunity to the viral vector. And that could limit the efficacy of the vaccine. And that was an issue for the CanSino candidate, where about 50% of participants in the earlier phase trials did have pre-existing antibodies to the vector. However the University of Oxford vaccine uses a chimpanzee adenovirus so that is one which humans do not commonly have pre-existing immunity to. Another issue though is that over time, with multiple doses, it is possible that you could develop immunity to the vector vaccine from a previous dose of the vaccine. So we are not sure what that means for booster doses, and that is something that is currently being studied.
 
Then for recombinant protein based vaccines, these ones as I mentioned use another organism, so such as a separate bacteria or virus to produce the protein antigen of interest, and then purify that. And there are other technologies. So Novavax actually has modified the gene for the spike protein, or modified their molecule so that it self-assembles into nanoparticles which actually resemble the size of the pathogen and therefore illicit a better immune response. And they have also got a novel adjuvant that they have included with their candidate. This is one of the vaccines which the Australian government has a purchasing agreement for. And another subunit vaccine is the University of Queensland vaccine. So what is interesting about that one is they have got what is called a molecular clamp, and so the S protein is like many proteins, it is inherently unstable and it undergoes changes, so this molecular clamp locks it into the pre-effusion form and what that means is it trains your immune system to recognise what the S protein will look like in its native form. It can also be produced as I mentioned without having to handle or access the live virus, and it produces a strong antibody response, but relies on adjuvants. It is also a proven technology. We have current existing vaccines based on this technology. But possibly a shorter duration of protection and scale up of manufacturing can be challenging.
 
And then finally, inactivated vaccines which everyone would be familiar with. These are relatively easy to produce so it is a proven technology that induces a strong immune response and there are potentially multiple antigens because you have got the whole pathogen and you increase the reactogenicity of the vaccine, but it requires biosafety level 3 facilities and is more complicated to scale up manufacturing.
 
Live attenuated vaccines. There are not actually any in clinical trials yet for SARS-Cov-2. But they do induce a very strong immune response and a longer duration of immunity. They do not require any adjuvant and it is again a proven technology. One of the potential benefits for both live attenuated and also for the viral vector vaccines, is that they might be able to be given intranasally and that means that you can trigger a mucosal immune response. That has some benefits including the potential for sterilising immunity if you can stop the virus from entering the upper respiratory tract, whereas many of the other technologies may be able to prevent severe infection, but it is not yet confirmed whether they will be able to provide that sterilising immunity. However, there are many other challenges to the intranasal route as well. Of course there are safety concerns associated with live vaccines, particularly for immunosuppressed patients and pregnant women. And it is time consuming to develop these vaccines and complicated to scale up manufacturing.
 
Sorry, I am rushing because we have so many slides to get through. And just a quick overview of all of the candidates based on the platforms. So you cans see here recombinant protein based are the most common technologies being used and other than live attenuated, there is otherwise quite an even spread, but looking at the vaccines that are in phase 3, you can see here, so quite a few viral vector vaccines and recombinant protein based vaccines.
 
So, just a quick look at the vaccine development timeline. So ordinarily, it would take 10 to 15 years to develop a vaccine and that is for many reasons. So one of which is funding, so developers would want to make sure they have had promising results at each stage before they invest the money to proceed with their development, whereas we have had unprecedented funding from governments and unprecedented collaboration between researchers that has seen a lot of this compressed. Also, it normally takes one to two years to get through the regulatory processes associated with vaccines, but regulators such as the TGA, FDA are all giving high priority to COVID-19 studies and vaccines and therefore that is also making it easier to progress research. And Kristine will talk more about the safety monitoring, but a couple of issues with this compressed timeline is, we currently, it is not easy to compare between candidates, particularly because we do not know what the immune correlates of protection are. So we do not know what titre of S protein antibody you need to say that you are immune to COVID-19. We also have not had time to study long term outcomes, so in particular, the duration of efficacy and safety outcomes, as well as rare outcomes which even in trials of tens of thousands can be difficult to detect and so therefore post-market surveillance is really important. Many of the studies understandably start off with only healthy, middle aged adults or you know, aged sort of 18 to 55 or so, although there is a decent number of studies including older adults. Special populations are often excluded. That includes pregnant women, younger children, people with significant medical comorbidities. So there will not be efficacy data for these groups until they are included in trials, though there are small sub-studies, so we have some immunogenicity data if researchers include those groups. Co-administration is also something. So next flu season we may have a COVID vaccine as well as flu vaccine, but we will not have data backing up the impacts of co-administration apart from one small sub-study but Novavax. And then mixed schedules. So if there is limited supply, if somebody has started off with one vaccine and then they do not have supply of that vaccine any more, we do not have data to know whether you can complete a course of a different vaccine. And then of course, the first vaccines to be licensed will not necessarily be the best.
 
So looking at the candidates that are most likely to appear on our shelves. The Australian Government has five separate agreements, so four are advanced purchasing agreements with vaccine developers, and Australia is also signed up to the COVAX Facility. So these are the four developers and we will have a little look at the vaccines that are tabled soon. And the COVAX Facility, sorry I will just put up the slide, so the COVAX Facility is led by the World Health Organisation Coalition for Epidemic Preparedness and Innovation, and also by Gavi, and is a collaboration of 188 countries that have pulled together their purchasing power to support the development of COVID vaccines and they have got 10 sort of selected candidates that they are projected to hopefully have two billion doses available by the end of 2021 and to ensure that these are equitably distributed to the participating countries. So, the Australian government has through COVAX Facility secured an agreement to supply enough vaccine for half of our population and that is in addition to the four separate purchasing agreements. And then a little bit there about Operation Warp Speed which is a private-public partnership with the United States government and vaccine developers.
 
So just moving on to the actual vaccine candidates. As of today, there are 212 vaccine candidates and 43 of those are in human trials, of which 11 are in phase 3 trials. And we would like to thank our colleague Zoe who has been working hard on gathering and updating this data. So the ones that are in human trials, you can see here the breakdown. So 11 now in phase 3 trials and as I mentioned, most of them, the most common categories are the protein based vaccines and quite a few viral vector vaccines.
 
And these are the candidates in the phase 3 trials. In green are the candidates that the government has advanced purchasing agreements for, so the Oxford vaccine, the Pfizer vaccine and Novavax. And we may also have access to the Moderna vaccine through the COVAX Facility. Looking at the age groups, you can see that the vast majority have only been tested in adults so far apart from a small sub-group in one of the Oxford vaccine phase 3 trials as well as the Pfizer vaccine. And we have seen within the last couple of weeks these recent preliminary announcements about phase 3 results.
 
And then finally, just a quick look at some of the vaccines characteristics. Oh, sorry about that. That should not have been overlying. That is hiding something.  So, Sammi I do not know if we are able to just remove that picture? So this is just having a look at some of the characteristics of these potentially available vaccines. So the Moderna vaccine unfortunately it is hidden, but that will need to be stored at minus 20° and then will be stable at fridge temperature for 30 days. The Pfizer vaccine should be stored at minus 70° and then stable at fridge temperature for five days. The Oxford vaccine and Janssen which is another adenovirus vaccine, and the protein based vaccines, can all be stored in the fridge. So that would make them much easier to distribute. As you can see, most of these candidates are delivered in a two dose schedule other than the Janssen vaccine. And all of these vaccines are intramuscular. So I will hand over to Kristine in case she wants to add more about the particular vaccine candidates.
 
 
Kristine:
 
Thanks very much, Ket, and well done on getting through all of that incredible amount of information. I mean it is an absolute smorgasbord dare I say it, of vaccine candidates, and it is almost impossible to believe that we have so many in phase 3 trials let alone two signalling such high efficacy at this stage, still in November. But I am going to talk to you about assessment for registration because as you can tell, you know, we have got two candidates that are getting close to submitting for registration to the US, they have signalled that they will be going to the FDA in the third or fourth week of November, and presumably soon thereafter to the EMA in Europe and hopefully the TGA in Australia very soon. So I am going to take you through what some of the next steps are. Just to mention again that we are going to be needing to look at these vaccines, not only for that antibody response, and you can see here that in respect to the gene segments of the virus, it appears that antibodies are particularly directed against that spike glycoprotein also against the nucleocaspid protein. Here is another diagrammatic representation. But there are also neutralising antibodies that Ket alluded to, particularly directed against the spike glycoprotein. So, why is neutralising antibody important? That is because it actually blocks the virus entry into the cell, and that is just the sort antibody that we want vaccine candidates to deliver. I saw a discussion in the chat about something called vaccine associated enhanced disease, and I will talk about that a little bit more in a minute. But if you just get any old antibody that gets in the way, but does not actually neutralise and block virus, you can actually get into trouble. So this neutralising antibody is really key. And then of course, most of the vaccine candidates, or a number of vaccine candidates, look like they are generating T cell responses which is really exciting, because we do not always see this with vaccines, and it looks like a particular property that is being engendered from the gene-based vaccines, so both the viral vector vaccines and the mRNA vaccines, as well as potentially from those vaccines that are protein-based with an adjuvant.
 
So we will be looking at those particular aspects when we look at the immune response, and that will be good but as we have mentioned already, you know, there is no magic measure of what an immune response is and in fact, it differs so vastly for every single vaccine preventable disease that we have, and indeed, even different vaccines for the same vaccine preventable disease. So we need to look at efficacy and this has been a huge discussion as you are aware, commitments to looking at efficacy along the way for all of the trials, although we do have both Russian and Chinese vaccine candidates that have apparently been put into use in those countries without efficacy data, and here I am using the term efficacy or effectiveness pretty much interchangeably but when we talk about that as vaccinologists, we tend to say efficacy refers to what comes out of the controlled clinical trials and effectiveness is what we measure in the real world after the vaccine is rolled out.
 
So how are the trials set up? Well, the primary outcome measure is symptomatic PCR-positive, COVIOD-19, so that is disease, that is laboratory confirmed. They are also looking at severe COVID, severe systemic illness using various definitions, looking at hospitalisation, ICU admission and death. Some of the trials are trying to look at asymptomatic infection, but that is hard and you can imagine it is hard, because how often do you swab someone or how often do you take their blood to measure antibodies? So some of the trials have had nucleic acid testing, you know throat swabbing, screening done regularly. Some are doing special antibody tests over periods of time to look at antibodies to the nucleocaspid where you will not expect that unless you had natural virus infection, because you only should see antibodies to spike.
 
They are obviously all looking at safety and what we call both reactogenicity, which is basically the profile of the vaccine within the first you know, five to seven days, but also serious adverse events and adverse events are of special interest.
 
Now, you know, many of the trials have been powered to be able to detect point estimates of around 50%, with a lower bound say around 30%. Some even a lower bound. So as you can imagine, people have been fairly conservative in their estimates and thinking, well if we get 50% which is around the ball park of flu vaccine, that would be good. Maybe if we got 70% that would be great. I think getting 90% which is you know, the preliminary data, has really been a nice surprise and we need to see the devil in the detail of course, but that is you know, what we are potentially looking at for these two vaccines.
 
So these are what we call event driven analysis trials. So this is why we cannot say to you, okay you know the study will be reported on the 1st December. You wait till the cases accrue and then you unblind the data and go, wallah! How many in the placebo, how many in the vaccinated are? But they have actually been occurring faster than expected because of the unfortunate fact they have been conducted where fact CoV-2 transmission rates are so high. Each candidate needs to have at least two months ideally of post-second dose safety data, and that is what the current candidates have signalled. And then there are going to be interesting challenges in the long term, because you would like to be sure that those who have done their best to be vaccinated but might have got a placebo would then be offered the vaccine as well. So it will be very interesting to see how that pans out. That is often a challenge with vaccine studies.
 
So this slide was made a few months ago by someone who is trying to guess when each of the vaccines would report their efficacy data, when they would signal that they had reached a number of cases and then could proceed to submitting to get regulatory approval. And you can see here that I am sorry, excuse me, that the Pfizer vaccine was not on this list, but that reported early September. And then there should be an animation here but the Moderna vaccine as Ket alluded to, reported just two days ago. Who is going to be next? Well maybe AstraZeneca. We are really interested in that result, because of course that is one of the vaccines with which Australia has one of the largest advanced purchase agreements. Maybe Novavax, although they did start their phase 3 trial a little bit later. So let us keep an eye out for these announcements. These are the two announcements of the last two weeks, Pfizer and Moderna, and although we do not have specific dates for the TGA submission, we do know that the TGA, our regulator, has granted a determination that says these two vaccines, so now the Oxford vaccine and the Pfizer vaccine, so the viral vector vaccine and the mRNA vaccine, that these two vaccines can go down what we call this provisional registration pathway. So the TGA has not said here, yes, you are going to be registered. They have said that they will allow the vaccines to be examined in this pathway that is very rapid, allows for a rolling submission and a review of data and will come up with a quicker decision but very importantly still with a high level of scrutiny for efficacy, safety and quality. So this is as you could imagine, pretty much underway now with rolling submission of information, when that is going to come out with a decision by the TGA we cannot yet predict.
 
So, remember that safety is not the absence of risk with anything we do in medicine. You know that every time you prescribe amoxicillin or an anti-hypertensive, it is the balance of benefits of risks, and that is no less true for vaccines. In fact, it is possibly more true because we give vaccines to healthy people to prevent disease rather than treating someone who is ill. So this slide is really just to say, that is what all regulators have in mind. We have here a committee called the Advisory Committee on Vaccines that helps advise the TGA on particular questions but the regulatory review process for every single country and every single one of these vaccines, notwithstanding some of the context I have already mentioned, is incredibly rigorous and I think we should be able as clinicians to hopefully give our patients confidence that these high standards of review have been met once we see vaccines start to become available. And they will not become available if these standards have not been met.
 
So what happens next? Let us assume, maybe early 2021 that we have an outcome and we have one or more vaccines that have been given the nod to be used in Australia, and we have them available. Who gets it first and how many people do we need to be vaccinated to get so-called herd immunity? Well, what I am showing you here is just some early advice from the WHO about some principles and priorities with COVID-19 vaccination. This is an overarching goal that vaccination must be a global public good and this is very important to see at the highest level of decision making and recommendation. They stated that the program should have safety and effectiveness to reduce transmission, morbidity and mortality, help minimise the disruption to the society and the economy and ensure equity. So this is a very big message coming through, but of course a very hard thing to achieve in reality.
 
The guidance from the WHO talks about three populations, so the higher mortality risk population, they are easy to imagine, older individuals, those with medical conditions. A high transmission or risk population. So here think healthcare workers, think people who might be you know, caring or providing services to those who are infected. And then essential population workers. Again, those who are absolutely critical to society’s functioning and were they to be infected, would give us some real challenges. So this is essentially where Australia has fallen also with priority populations, and I you can see the overlapping sort of Venn diagram here. But I can take you through some of that.
 
Now we know that there has to be limited doses in the beginning. We cannot just go from zero to billions of doses, even though the factories have already been built and the doses are already being made before regulatory approval has been given. These are the sorts of risks that have been undertaken but of course we will still have limited supplies of vaccine initially. And here is just one prediction from WHO that shows us you know, where we go to billions of doses, but of course you know, let us just hope we can get there soon in terms of having at least these number of doses.
 
But there are many unknowns. And this includes whether the vaccine is going to be transmission blocking, whether it protects just predominantly against severe disease, will it protect also against mild disease? We do not know this yet from any of the data but we will learn more. And what is the overall impact on transmission and disease taken together? Will we see both, and if so, at what level? Particularly with the efficacy in older individuals and individuals with comorbidity. And I have already mentioned that benefit-risk assessment.
 
So without going into this in a lot of detail, this is just a graphic that talks about how we achieve herd immunity, and the most important message to take away here, and I will show you the panel on the left first, because this is when you pretty much have a naïve population, so not many people infected, which is still essentially most of the world, the first year of vaccination ideally you would like a vaccine with a lot of efficacy here on the bottom right moving up to you know, 100%, wouldn’t that be great, with a longer duration of protection and in that case, you will need fewer people vaccinated to achieve this ceiling or threshold of herd immunity. But if in fact we have a lower efficacy vaccine, perhaps it does not last for as long, you will need to you know reach nearly 100% of the population which we all know is very challenging. Things get a little bit easier if you have reached a large proportion of the population in subsequent years once you get to a bit more of a steady state which is what panel B shows. But you know, two of these things are kind of unknown at the moment, as indeed is how many people we will have vaccinated. But these three elements are very critical.
 
Now I am not going to spend a lot of time on these for sake of today’s discussion, but I wanted to give you the flavour of the fact that people are already modelling like crazy without necessarily all of the model inputs that we need, but looking at how many deaths can be prevented, how many quality adjusted life years et cetera, et cetera. What would happen if we went and vaccinated healthcare workers versus residents you know, how would that look with the number of people vaccinated? What about modelling by vaccinating by occupation and how would that impact upon our economy and the economic impact. So you know, none of these models is perfect, and they are less perfect when they do not have really clear inputs such as vaccine effectiveness estimates, but you will see a lot more coming out in respect to modelling as we get vaccine trial results available.
 
But safety is on everybody’s minds. And you know this. We all know this. We deal with it every day with our patients and we see it now pretty much you know, every day or every second day in the press. So over here, the headline, Oxford vaccine volunteer dies, marking the first death reported in a coronavirus vaccine trial. Well, that already makes me feel anxious. You only have to read down one paragraph to see, following careful assessment there have been no concerns about the safety of the clinical trial and the independent review in addition to the Brazilian regulator recommended that the trial should continue. So you know, we know that death occurs, and death occurs in vaccine trials as well as in people who are not in vaccine trials. So, you know I think that we are going to be delivering this vaccine in a really heightened and complex environment in respect of messaging, anxiety and everything else. We have already seen it with the way in which the trial data has been reported.
 
Just a quick plug out to the fact that there are a lot of Australians that are working, providing and inputting into advice at the global level on both safety and also on recommendations variously for Australians involved with the strategic advisory group of experts on the vaccination at the WHO level. So, a bit of a shameless plug there.
 
But it is important to have these two things in mind, and I just wanted to mention them to you. So, what is an adverse event following immunisation? And I always say remember the following, not adverse event caused by, immunisation, or adverse reaction to immunisation. What an adverse event following immunisation is, is any medical occurrence that comes after the jab, that does not necessarily have a causal relationship with it. So you know you will see this. You start someone on a medicine and the next day you know, they report a rash started, they come back and see you a week later, and was the rash from the medicine? Well it is often hard to tell. Same with vaccination. Adverse events of special interest are, many of these events where we often do not know the aetiology. And what happens then, well you look to what could the cause have been? And this is where unfortunately, vaccines are often invoked as a cause. So, it may be that we have special interest events because there is a certain property to the vaccine, so think something about you know, intussusception which is a bowel blockage, and rotavirus vaccine. Well, that is an adverse event of special interest. Or, it just may be that we know that you know, serious events like neurologic conditions are going to cause concern if they occur shortly after the vaccine has been given, you know, irrespective of whether they were seen in clinical trials or were not seen in clinical trials. So these are events for which it is appropriate to have ongoing monitoring, rapid communication and really careful both epidemiologic and biologic studies to try and look at causal associations.
 
So there have been a number of special events that have been listed as being possibly relevant to COVID-19 vaccines for all sorts of reasons. So, the concept that you might get enhanced disease and I will talk a bit more about this in one minute, or the multi-inflammatory syndrome, these sort of vasculopathies that we know the virus itself can cause. Respiratory distress of course, things like anosmia, ageusia, you know dermatological manifestations which have also been seen in COVID-19 itself. This is not because we intend to use live vaccines, in fact you have heard from Ket that there are no live vaccines in development at the moment. This is just because these are kind of look-alike syndromes that may indeed occur without COVID-198 being around and they may occur with COVID-19 being around, so many countries where vaccine will be rolled out but the virus will be still raging through those communities we anticipate. So you will be seeing COVID infection patients at the same time as COVID vaccinated patients and you know, this will be the background really on which vaccine is delivered.
 
So what is vaccine-associated enhanced disease? So one of the chatters early on mentioned this. It is really important that when SARS was studied as a vaccine in mice and indeed also in a murine model, oh sorry, a feline model in cats, an indeed for one of the MERS candidate vaccines, these are the animal studies, there was some evidence that the lung pathology was actually worse in the vaccinated animals. And so hence the term vaccine-associated enhanced disease, or enhanced respiratory disease. And this can come about for a few different reasons. It can come about because that non-neutralising antibody is generated or that you get clumping and antibody deposits in the lung, or that you get aberrant kind of T cell responses that actually you know, cause harm rather than good. So it is a complex entity that can be from a few different immunologic mechanisms. But the really good news, the really good news here, is this has not been seen in a myriad of animal studies for the SARS-CoV-2, the COVID-19 vaccines. And let me tell you that there has been about six different animal models, so many different animal models. Animal models particularly designed to look at this phenomenon. So not seen in the animal model studies of which there have been hundreds and hundreds really so far. Many not published, but I am part of a group that occurs late at night every week and presents on these. And then the second thing is, it has not been seen so far as hinted at in clinical trials. Nonetheless, the safety community really wants to follow this as a potential outcome very closely, and studies have been devised around the world to do this, which basically means looking to see if COVID-19 occurs in people who are vaccinated, and if it does, is it worse than it would have been if they were not vaccinated? Complicated studies to set up, but really, really, really important.
 
Okay, so we will just quickly go through some of the safety data. It is hard to present this in a lot of detail, so I will just go back here. This is the AstraZeneca phase 1-2 data. This is available online. And remember this is the viral vectored vaccine. Now the comparator here was not actually placebo, it was meningococcal ACWY vaccine, and they gave some people paracetamol and others not. And now if you compare that with, I am sorry, the actual vaccinated participants, and you look up the top to see what I am actually showing you, chills, fatigue, fever, feverish headache, joint pain, malaise, muscle ache, you can see well paracetamol firstly did not make too much of a difference. People noticed they had this vaccine more than they certainly did if they had the meningococcal vaccine. And you know, it did knock a few people around a bit with respect to tiredness, headache for a few days, but not a lot of severe reactions. So I think our patients will tell us yes, doc I know I got the vaccine, but certainly no serious adverse events here. And they did give a second dose only in a small number of participants, and there were lower rates of adverse events in those participants.
 
What about the Pfizer data? Well this is a really busy slide, I apologise. But if you just look along here, you can see participants 18 to 55, and you look at the bottom row which is, there were two candidates studied here and they have selected the number two, the B2 dose candidate because it actually had the better safety profile. So, we might remember, Ket showed you the immunogenicity data. There was not a lot of difference in the immunogenicity of these two candidates, the B1 and the B2, but the B2 had a much better safety profile, you know, rates here of fever, fatigue, chills, post dose one and dose two, which were reasonably high but still acceptable and not many at all in that sort of severe category. And then of course, in the older age group as we see with other vaccines, generally better tolerated. So again, look down here to the bottom which is the more favourable safety profile, and this is the candidate that has been studied in stage 3 trials. And over here, you can see the same types of set up in the graphs, but here we are talking about injection site reactions. So, pain, redness, swelling. And again, much better tolerated in the older age group, 65 to 85 years, which is at least some good news.
 
Okay, so there is a National Pharmacovigilance Plan. It is still under development with the TGA. It has all the main goals of other vaccine safety systems globally to fully characterise the profile once in use to detect adverse events et cetera, et cetera, and I will not go through all of this. But important to communicate what I think this is going to be a very important challenge and will we all have an important role in this. In Australia we will have multiple modalities of safety surveillance. So this is another thing to be aware of, and I think talk to patients about. There will be the usual passive or spontaneous reporting system, and that is where everyone I hope is participating. Active surveillance and whilst these are under consideration we very much hope and expect that the AusVaxSafety system which I will tell you about in a minute will be used. Studies to look at what the background rates of some of these special interest events are. So, how many cases of multiple sclerosis occur every week? Well, we you know, how many would we expect to see within a few days after vaccination? What about transverse myelitis? What about GBS or rash or you know, I mean unusual rash obviously, we would have to be thinking about say vasculitis. These types of things we would like to know the background rate. And of course, international linkages and communication plans.
 
So, I hope you are aware of the AusVaxSafety system. It is really easy to find, just google search AsuVAxSafety.org.au, and these two fabulous tools, Vaxtracker and SmartVax, and if you jump on the SmartVax website, you can actually just join up, they can enrol your practice remotely. It is automated data extraction out of your practice management software, and your patients get a tailor made SMS message and they answer a survey. They say yes or no, whether they had an adverse event. The no is really important. It gives us a denominator. The responses are all de-identified and monitored and the results put up on the website and you can follow weekly data there for lots of vaccines, say for example flu vaccine we had 300 thousand people answer this survey last year.
 
So, what will go wrong? What do we need to be prepared for? One of the things I think we need to be prepared for is this potential for a temporal association. So, something bad will happen, someone will have been vaccinated in the days or a week or two before and people will be concerned and I think that is very normal, but we need to proceed with caution. So we need to have all of the safety frameworks that we know around us, we need to be very clear that each case will be looked at closely, that there will be causality assessment done, that there are special studies underway which will inform our thinking as each case is assessed and to not necessarily you know, throw up our hands and panic, but to really view this as a scientific challenge. Because there will be temporal associations and I think Australia is extraordinarily well placed to be able to look at this very closely. I just say at the coal face level, just be aware of jumping to conclusions about causality but make sure you report those events by the same token, and keep up to date with the safety profile.
 
So this was released on Friday, Australia’s COVID-19 Vaccination Policy. There has been a lot of focus obviously on R and D, purchase and manufacturing partnerships, regulation and now we are moving into the administration program design and monitoring. And this includes priority groups. I have already mentioned some of these and there are some challenges in the data that we have talked about, coadministrating Ket has talked about, issues with cold chain, the need to ensure two doses and we absolutely will have multidose vials. So Australia can deal very well with these. We did it for Panvax. There will only be multidose vials in the whole of the world for a good period of time, because it is not possible to manufacture billions of individual doses. But there will be you know, strong guidance coming out of this and really clear instructions on how to use this. It always does cause a little bit of wastage, you know and it does pose a bit of a challenge for setting up your clinic so you can minimise wastage of course.
 
So we think the program will start in quarter one 2020. That is the plan at the moment. But we do not know which vaccine it will be yet. There are likely to be other vaccines added in. It is likely that the registration will only be in adults at first, and you know, this is going to be a bit of a challenge particularly say for remote locations and I think we have talked about these priority populations, those with increased risk of exposure, increased risk of severe disease, and in critical services. Free for all Medicare eligible Australians and almost all visa holders except those tourist temporary visas. The specific clinics. So I would imagine, and I think everybody has talked about this, as the very few first doses come on line, the number of clinic were the vaccine is going to be able to be given is going to be limited. That will obviously expand out as more doses become available. But I think even though this is going to be a very shared Commonwealth, state and territory program, we know that here at New South Wales Health immunisation you know, group will be working closely with you to step through a lot of where the vaccine will go first. And obviously, the work places where there are these high risk populations like hospitals and aged care facilities are going to be very important.
 
 
Ketaki:
 
Kristine, someone has just pointed out that previous slide should say quarter one, 2021.
 
 
Kristine:
 
Oh, 2021. Exactly, what a good idea. Or we can go back in a time machine and not even have the pandemic, because we will have a vaccine already. I love that. And maybe that really was wishful thinking.
 
 
Ketaki:
 
That was the plan.
 
 
Kristine:
 
Okay, well what can I do to be COVID vaccine ready? And I think I have even updated this slide, but I have not got the updated version here, but start to think about your own practice. I would really encourage this, we know vaccines are biologic products, they need an enormous amount of respect. There will be training modules coming, detailed guidelines coming, but start to think, are you hooked up to the Australian Immunisation Register? Are you getting regular software updates? Are you absolutely sure your data is transmitting? Do you enter it in the right place? This is going to be mandatory reporting to the register, not vaccination mandatory, but reporting mandatory, and that is incredibly important because you know, we do not want to be missing vaccines, not know who is vaccinated, vaccinating someone three or four times. Are you ready with PRODA? Because this is a new way of ensuring linkage to the AIR and there are a lot of tutorials on this which I know the team can report you to. Do you know how to report adverse events? Can you do so easily and where do you go to get help? So, I would particularly encourage you to go to you know, know your public health unit and how they can help you, and of course our 1800 NSWISS, so New South Wales Immunisation Specialty Service, and I apologise that it is not on this slide. Again, we will need to learn about multidose vials, cold chain maintenance and this will have to be followed to the T. You know, some of these mutlidose vials do not have a preservative because it is not compatible with the vaccine itself, so you know, getting your practice ready to operate in a very slick way. You can start now in a non-specific way, but really have everybody ready. Accrediting your immunisation nurses. Getting you know, cold chain monitoring up to date. You know, all of these really critical elements.
 
So just a couple of take home messages. The program is starting soon. We do not know which vaccine, but we know which probably basket it will come from. There are many details still to come. Things to start to get ready. There is the 1800 NSWISS number. And obviously there is still quite a bit more to learn about things, logistics, cold chain, ordering, but that will come. And I think you know, we have an incredibly strong primary care general practice workforce, so my congratulations go out to all of you for everything you do, and we are really looking forward to seeing a highly effective program rolled out in Australia hopefully very soon, and building on the success we have already had with controlling the virus and the part you have played in that. So thank you very much everyone.
 
I have to end with this, because it is a favourite, but this tells you how even more than 200 years ago, the public was sceptical of small pox vaccinations, that you know, people would grow cow parts from their bodies. Now we have eradicated small pox. I personally think we are unlikely to eradicate SARS-CoV-2 from the planet. We can talk about that separately, but we certainly, you know, we certainly want to be really on top of all our messaging and our systems so that we do not, you know, we do not succumb to any mis- or disinformation like this. Thank you very much, everyone.
 
 
Sammi:
 
That is great, thanks so much Kristine and Ketaki. We do have just a few minutes left, so we might field some of the questions that have come through here. Some have already been responded to via typing online. We have got one that has come through, do we know anything let us say for the leading ones at this stage obviously as you mentioned at the start there are a large number that are in the testing phase, but for the ones that are currently I guess leading the charge, do we know anything about the efficacy and safety if it is to be given to pregnant women at all?
 
 
Kristine:
 
So at this stage we think there is likely to be very little data on pregnant women. We know some women will have become pregnant around the time or may have just had conception around the time that they were vaccinated, and those women are being followed very closely, but they will not be in really large numbers or enrolled in a prospective controlled way. I am sure that there will be vaccine studies in pregnancy happening more down the track, but I think it is important to remember that there are no theoretical concerns. There are no theoretical risks about the platform technologies that we will be using and pregnant women, so you know, some of them will contain adjuvants. Now we have used adjuvants in pregnant women before of course. Adjuvants are things like aluminium, but also you know adjuvants that go along with HPV vaccines which we know have been used in thousands and thousands of pregnant women, even though they are not routinely recommended. So we do not have any express concerns at this stage. There will be limited data and it is going to need to be clinical decision making but of course we need to see what the regulatory advice will be as well, and the clinical advice.
 
 
Sammi:
 
Fantastic. And there is another one that has come through that I would say we know the answer to this, is yes. Someone has kind of commented and asked whether we think there will be people that will not want to take the vaccine and Kristine I am sure you would agree that the answer to that is yes, like with any other vaccine there is going to be people that for their own reasons do not want to take it. And as a GP, what you can do is inform them of the risks and the benefits and what the science behind it says. And unfortunately, that is all you can do.
 
 
Kristine:
 
Look, Ket might want to answer as well, but I think we should you know, encourage our patients to have questions. I think we should you know, in so much as we can really be armed with the best facts to give them that information that you are alluding to, and you know, I have got a lot of friends who come up to me and say, oh I will not be having it yet. And I say to them, well that is fair enough, because we do not know anything about it yet. You know? We have still got a lot to learn. And we had to learn it quickly, but it has been done in a rigorous way and I think you know, we want to encourage our patients to have questions, there will be a lot of frequently asked questions. We are going to put our own early FAQ up on our own NCIS website, hopefully in the next week to 10 days just to start to point people to something, because people that do not like to make decisions when they do not have a lot of information will have a lot of information by the time the vaccines get rolled out. Someone asked why March? You know, we do not know yet whether it is March, February or April. But I think it will not be long behind say even somewhere as you know, bold in the way they are making statements like the United States. It is all relative and the timeframes we are dealing with are incredibly short.
 
 
Sammi:
 
Absolutely. Alrighty, that does tick us over to 8:30 so I just want to thank both Kristine and Ketaki again for joining us this evening, and also to everybody that joined us online. Up on your screen at the moment is a review of the learning outcomes that we hope you are better able to do following this webinar. Obviously there is still a lot of unknowns and we definitely do not expect anyone to be an expert in COVID from watching this, but thank you so much for joining us and to our presenters this evening. We do hope you enjoy the rest of your evening.

Other RACGP online events

Originally recorded:

18 November 2020

Vaccination of the Australian population against the SARS-CoV-2 virus (COVID-19) when a vaccine becomes available, is a key national pandemic response strategy outlined in the Australian Health Management Plan for Pandemic Influenza (AHMPPI) and Australian Health Sector Emergency Response Plan for Novel Coronavirus (COVID-19). Since the identification of the COVID-19 virus in early 2020, vaccine manufacturers have been working on developing effective vaccines. This webinar will provide an update on the current state of vaccine development, the progress of human trials and program considerations relating to allocation, safety, and efficacy.

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