Transcript of COVID-19 vaccine - where are we at?

Sam: 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 recognize the traditional custodians of the land and sea on which we live and work and we pay our respects to elders past and present.

Just some housekeeping quickly, so you know how to interact with us and with your control panel this evening. So your control panel will appear as a black bar at the bottom of the shared presentation screen. If you can't see it just take your cursor and hover it over the bottom of your screen and that should make it pop up and your control panel has your audio settings your raised hand functions and most importantly, your questions box. Okay everybody has been placed on listen only mode, this is to make sure that learning isn't disrupted by any background noise. As I mentioned though there is a question box there so please do send us your questions and comments as they arise throughout the session we will do our best to respond to them all online but in the interest of time it isn't always possible so what we'll do is we'll post an email address for you at the end of the session where you can send through any unanswered questions relating to our learning outcomes and we'll get back to you offline.

I would like to formally introduce our presenters for this evening now, Professor Kristine Macartney is a pediatrician 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 Center for Immunisation Research and Surveillance, a pediatric 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're also joined by Dr Ketaki Sharma, Ketaki is a general pediatrician and a Staff Specialist at the National Center for Immunisation Research and Surveillance. She is part of the NSW Immunisation Specialist Service and reviews children who have experienced an adverse event following immunisations. She is also currently undertaking a PhD focused on optimisation of antenatal vaccination. 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 prioritization and allocation and discuss the safety and efficacy of a pandemic vaccine and the associated monitoring processes. So I'll hand over to you now Kristine to get us started.

Kristine Macartney: Wonderful, thank you so much Sammy and welcome everyone and thank you so much for having us both, Ket Sharma and myself, we're honored to be here. I've just got to make sure that I have my correct view options on here, I think I seem to have a small view so I'm going to see if I can fix this. There we are.

Okay so I too would like to acknowledge the traditional owners of the land on which we're meeting and acknowledge elders past, present, emerging and any of the Aboriginal and Torres Strait Islander people that are joining us today.

As Sammy mentioned we're going to discuss a number of the COVID-19 vaccine platforms and talk a little bit about the different technologies uh focusing on some of the leading candidate vaccines talk about immunogenicity and efficacy assessment touch on implementation and prioritization 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 with a COVID-19 vaccinal vaccines. So I'm going to now hand over to Ket and I think she'll be able to take control of the screen now and take you through some of the vaccines.

Ketaki Sharma: Thanks Kristine, something hopefully that works, Yeah there we go. So I'll dive right in. So to start off with I'm just going to give you an overview and then we'll go in depth into each of the platform technologies that are currently being used. Sorry someone's saying there's a lot of lag and breaking up. Could someone just confirm are you able to hear me?

Sam: You're coming through loud and clear Kateki. The sound can be related to internet connection so carry on and I'll message them.

Ketaki: Great, thank you. So just a big picture, there's sort of two groups of platform technologies you can either make a vaccine where you're delivering the antigen directly in the vaccine and so that's the group on the left where you could have a whole virus vaccine either live attenuated or inactivated and everyone would be familiar with those or protein-based vaccines where you're 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'll 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 then nucleic acid vaccines are either RNA or DNA and I'll go in a little bit more detail of how they actually get the gene into the host cell. So viral vector vaccines, there are actually two licensed ebola vaccines that use viral vectors and it's also a technology that has been used for some years. In gene technology nucleic acid vaccines although they've been under development for decades there are currently no licensed DNA or RNA vaccines for use in humans.

So now having a look at the actual SARS-CoV-2 virus, what are the actual antigens that you might use? You can see around the border of this diagram are the the orange spike, so that's the spike protein and so you would have seen that represented everywhere in the media and that is the protein that contains the receptor binding domain that actually attaches to the a2 receptor and this is by far the most common antigen of choice in all of the candidate vaccines and this is supported by the research that was done into the original sales virus one and that 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 and some vaccines might only have the receptor binding domain fragment then inactivated vaccines would have the whole virus but it wouldn't 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 so envelope protein and nuclear protein and matrix protein and then the vector vaccines here use another virus to carry the gene for the sprites by protein inside and the DNA vaccine uses a plasmid to carry the gene for the spike protein and the RNA vaccine here, I'll just talk a little bit more about it. It's in it's encapsulated and has the MRNA inside, so looking at closely at the MRNA vaccines these are very topical right now because they're the ones that you would have seen in the news some recent announcements by moderna and pfizer which we'll talk about later so what an MRNA vaccine is is a piece of MRNA that's hard to get into the cell because RNA gets broken down very easily by circulating ribonucleases and it's it's very it's inherently very prone to degradation so what they've done is they've encapsulated it in these lipid nanoparticles that helps it to end to be protected against degradation and also helps it to enter the host cells and so these RNA and even DNA they can be taken up by when you inject it by myocytes but in particular if they're taken up by antigen-presenting cells that's when you're 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 don't actually need to have access to the virus itself so you don't need sort of special bio safety and level 3 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're not established technology 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 currently recommended to be stored at minus 70 degrees though 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 degrees and then stable in the in the fridge for about 30 days and 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 a result from a phase one two study so not the phase three study that was the interim analysis that was recently in the news um having a look you can see here on the right hand side this is the antibody levels in convalescence theorem so from patients who have recovered from carbon 19 infection and then you can see here the blue columns are the the current vaccine candidate that's been selected um in adults aged 18 to 55 and then in older adults 65 to 85 and looking at spike protein binding antibodies on the top and neutralizing antibodies on the bottom and basically this diagram itself the graph is just here to show you that it did induce some antibody levels that were comparable to those of people who had recovered from COVID-19 infection oh sorry and then we had the announcement on the 9th of November that they've done an interim analysis of their phase 3 study and reported not more than 90 efficacy so that's a very exciting announcement a great milestone and Kristine will be talking about that later.

So then the next MRNA candidate that's been in the news is the Moderna vaccine, so that is also an MRNA vaccine that's encapsulated and encodes for this 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've 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 could either be naked or incorporated into a plasmid but it's very hard it's not easily taken up by cells once it's 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 rapid to to manufacture and to scale up they're quite stable so the candidate vaccines produced by INOVIO and there's another one Symvivo, can be stored at room temperature and the Symvivo, which is a phase one DNA, phase one 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 and adjuvants and there are potential safety issues because the DNA will obviously be taken up into the nucleus and and there are currently no licensed DNA vaccines in humans. So limited knowledge about, limited experience with that platform.

Viral vector vaccines either replicating or non-replicating, so these are the technologies that use a carrier virus. So common ones include adenovirus and then incorporate the gene for the spike protein into the carrier virus, the replicating ones can then propagate to a degree so it's 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 humeral 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 as well 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 cancino 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's one which you humans don't 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 I'm not sure what that means for booster doses and that's 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 there are other technologies so nozabax is actually has modified the gene for protein or modified their molecule so that it self-assembles into nanoparticles which actually resemble the size of a pathogen and therefore elicit a better immune response and they've also got a novel adjuvant that they've 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's interesting about that one is that they've got what's called a molecular clamp and so the s protein is like many proteins it's inherently unstable and it undergoes conformational changes so this molecular clamp locks it into the the pre-fusion form and what that means is it trains your immune system to recognize what the s protein will look like in its native form it can also be produced as i mentioned without having to handle access to live virus and induces a strong antibody response but um relies on adjuvants it is also a proven technology we have currently 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 it's a proven technology that induces a strong immune response and there are potentially multiple antigens because you've got the whole pathogen and though that could also increase the reactorgenicity of the vaccine but it requires biosafety level 3 facilities and is more complicated to scale up manufacturing live attenuated vaccines there aren't 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 don't require any adjuvant and it's 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 and that has some benefits including the potential for sterilizing immunity if you can stop the virus from entering the upper respiratory tract whereas many of the other technologies will may be able to prevent severe infection but it's not yet confirmed whether they will be able to provide that sterilizing immunity however there are many other challenges to the intranasal root as well and of course then 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. I'm rushing because we have so many slides to get through.

And then just a quick overview of all of the candidates based on the platform so you can see here recombinant protein-based are the most common technology being used and that other than a live attenuated there's otherwise uneven spread but looking at the vaccines that are in phase three you can see here so quite a few viral vector vaccines and a recombinant protein based vaccines so just a quick look at the vaccine development timeline ordinarily it would take 10 to 15 years to develop a vaccine and that's for many reasons so one of which is is funding so developers would want to make sure that they've had promising results at each stage before they invest the money to proceed with their development whereas we've had unprecedented funding from governments and and unprecedented collaboration between researchers that have seen a lot of this compressed also it normally takes one to two years to get through the regulatory process associated with vaccine 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's not easy to compare between candidates particularly because we don't know what the immune correlates of protection are so we don't know what tita of s protein antibody you need to say that you are immune to COVID-19. We also haven't got time haven't had time to study long-term outcomes so in particular um 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-marketing surveillance is really important many of the studies understandably start off with mostly only healthy middle aged adults or you know age sort of 18 to 55 or so although there's a decent number of studies including older adults but special populations are often excluded that includes pregnant women, younger children, people with significant medical comorbidities, so there won't be efficacy data for these groups until they're included in trials, though there are small sub-studies so we may have some immunogenicity data if researchers include those groups.

Co-administration is also something so next flu season we may have this COVID vaccine as well as flu vaccine but we won't have data backing up the impacts of co-administration apart from one small firm study by nova backs and then mixed schedule so if there's limited supply and somebody's started off with one vaccine and they don't have supply of that vaccine anymore we don't have data to know whether you can complete a course with a different vaccine and then of course the first life vaccines to be licensed won't 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 advanced purchasing agreements with vaccine developers and Australia's also signed up to the COVAX facility so these are the four developers we'll have a little look at the vaccine to the table soon and the COVAX facility. I'll just support the slide.

So the COVAX facility is led by the World Health Organization Coalition for Epidemic Preparedness and Innovation and also by Garvey and is a collaboration of 188 countries that have pulled together that purchasing power to support the development of covered vaccines and they've got 10 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 that facility secured or secured agreement to supply enough vaccine for half of our population and that's in addition to the four separate purchasing agreements um and then the little bit there about operation warp speed was the 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 acting candidates and 43 of those are in human trials of which 11 are in phase 3 trials and we'd like to thank our colleague Zoe who's 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 three phase three trials in green are the candidates that the government has advanced purchasing agreements for so the Oxford vaccine fires a vaccine and those are facts and we may also have access to the moderna vaccine through the COVAX facility um looking at the age groups you can see that the vast majority have only been tested tested in adults so far apart from a small subgroup in one of the Oxford vaccine phase 3 trials as well as the Pfizer vaccine and we've seen within the past couple of weeks these recent preliminary announcements about the phase 3 results and then finally just a quick look at some of the vaccine characteristics oh sorry about that oh that shouldn't have been overlying that's hiding something um so sammy I don't know if we're able to just remove that picture but so this is just having a look at some of the characteristics of these potential potentially available vaccines so the Moderna vaccine unfortunately it's hidden but that will need to be stored at minus 20 degrees and then we'll be stable at fridge temperature for 30 days the Pfizer vaccine as mentioned minus 70 degrees and they're stable at bridge temperature for five days Oxford vaccine and Jansen 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 two-dose schedules other than the jensen vaccine and and the and all of these vaccines are intramuscular and so I'll 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's an absolute smorgasbord dare I say it of vaccine candidates and it's almost impossible to believe that we have so many in phase three trials let alone two signaling such high efficacy at this stage still in November so I think I'm going to just now take over I think the the slides oh and whoops I've already put them into different mode there but I'm going to talk to you about assessment for registration because as you can tell you know we've got two candidates that are getting close to submitting for registration in to the US they've signaled 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'm 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 you can see here that in respect of the the gene segments of the virus it appears that antibodies particularly directed against that spike glycoprotein also against the nuclear capture protein here's another diagrammatic representation but there's also neutralizing antibodies kit alluded to particularly directed against the spike like a protein so why is neutralizing antibody important be that's because it actually blocks the virus entry into the cell and that's the sort of antibody that we want to vaccine candidates to deliver I saw a discussion in the chat about something called vaccine-associated enhanced disease and I'll talk about that a little bit more in a minute but if you just get any old antibody that gets in the way but doesn't actually neutralize and and block virus you can actually get into trouble so this neutralizing antibody is really key and then of course most of the vaccine candidates are a number of vaccine candidates look like they're generating t-cell responses which is really exciting because we don't always see these with vaccines and this looks like a particular property that's 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'll be looking at those particular aspects when we look at the immune response and that'll be good but as we've mentioned already you know there's no magic measure of what an immune response is, 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're aware commitments to looking at efficacy along the line along the way for all of the trials although we do have both Russian and Chinese vaccine candidates that are have apparently been put into use in those countries without efficacy data and and here I'm using the term efficacy or effectiveness pretty much interchangeably but when we talk about that as a vaccinologist we tend to say efficacy refers to what comes out of the control clinical trials and effectiveness is what we measure in the real world after the vaccines rolled out so how are the trials set up well the primary outcome measure is symptomatic pcr positive COVID-19. So that's disease that is laboratory confirmed they're also looking at severe covered severe systemic illness using various different definitions looking at hospitalization ICU admission and death some of the trials are trying to look at asymptomatic infection but that is hard and you can imagine it's hard because how often do you swab someone or how often do you take their their blood to measure antibodies so some of the trials have had nucleic acid testing knows, you know throat swabbing screening done regularly some doing special antibody tests over periods of time to look at antibody to the nuclear capsid where you won't expect that unless you've had you know natural virus infection because you only should see anybody to spike they're obviously all looking at safety and what we call both reactogenicity which is basically the the profile of the vaccine within the first you know five to seven days but also serious adverse events and adverse events of special interest now you know many of the trials have been powered to be able to detect point estimates of around 50 percent with a lower bound say around 30 some even a lower bound so you know as you can imagine people have been fairly conservative in their estimates and thinking well if we get 50 which is around the ballpark of flu vaccine that would be good maybe if we got 70 that would be great i think getting 90 which is the you know preliminary data is has really been a nice surprise and we need to see the devil in the detail of course but that's you know what we're potentially looking at for these two vaccines so these are all what we call event driven analysis trials so this is why we can't say to you okay you know the the study will be reported on the first of December you wait till the cases accrue then you unblind the data and go voila how many in the placebo how many in the vaccinated arm but they've been actually occurring faster than expected because of the the unfortunate fact that they've been conducted where SARS-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's what the current candidates have signaled and then there are going to be interesting challenges in the long term because you would like to be sure that those who've done their best to be vaccinated might have got a placebo would then be offered the vaccine as well so it'll be very interesting to see how that pans out. That's 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, oh I'm sorry, excuse me that the Pfizer vaccine wasn't on this list but that reported early September and then there should be an animation here but the modern vaccine has kept alluded to reported just two days ago who's going to be next well maybe AstraZeneca and we're really interested in that result because of course that's one of the vaccines with which we 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's keep an eye out for these announcements. These are the two announcements of the last two weeks Pfizer and Moderna and although we don't have specific dates for the TGA submission, we do know that the TGA, our regulator has granted a determination that says these two vaccines are 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 hasn't said here yes you you're going to be registered they've said that they'll 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's 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 or an antihypertensive it's the balance of benefits over risks and that's no more true you know no less true for vaccines in fact it's 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 that's 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 contexts I've already mentioned is incredibly rigorous and I think that we should be able as clinicians to hopefully give our patients confidence that these high and you know standards of review have been met.

Once we see vaccines start to become available and and they won't become available if these standards haven't been met. So what happens next? Let's assume maybe early 2020 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 have vaccinated to get so-called herd immunity? Well what I'm showing you here is just some early advice from the WHO about some principles and priorities with COVID-19 vaccination. This is a 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, mortality, help minimize 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 of the who talked about three populations so the higher mortality risk population they're easy to imagine older individuals, those with medical conditions, a high transmission or you know risk population. So here you 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 to be infected would would give us some real challenges. So this is essentially where Australia's fallen also with priority populations and I can and you can see the overlapping sort of Venn diagram here but I can take you through some of some of that.

Now we know that there has to be limited doses in the beginning, we can't 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 sort of risks that have been undertaken but of course we will still have limited supplies of vaccine initially. And here's just one projection from WHO that shows us you know where we go to billions of doses but of course you know let's just hope we can get there 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 don't know yet this yet from any of the data but we will learn more and what's the overall impact on on transmission and disease taken together will we see both and if so at what level, particularly what would be the efficacy in the in older individuals and in individuals with co-morbidity?

And I've 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'll show you the panel on the left first because this is when you pretty much have a naive population so not many people infected which is still essentially most of the world, the first year of vaccination ideally you'd like a vaccine with a lot of efficacy, here on the bottom right moving up to you know close to 100 if we you know 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 doesn't last for as long you'll need to you know reach nearly 100 of the population which we all know is is very challenging. Things get a little bit easier if you've reached a large proportion of the population in subsequent years once some you get to a bit more of a steady state which is what panel b shows but the you know the 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'm not going to spend a lot of time on these for the sake of today's discussion but I wanted to give you the flavor of the fact that people are already modeling modeling 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 etc etc what would happen if we went and vaccinated healthcare workers versus residents you know how how would that look with the number of people vaccinated, what about modeling by vaccinating by you know occupation and how would that impact upon our economy and the economic impact? So you know none of these models is perfect and they're they're less perfect when they don't have really clear inputs such as vaccine effectiveness estimates but you'll see a lot more coming out in respect of modeling 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 every day with our patients and we see it now it 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 deaths reported in a coronavirus vaccine trial, well that that already makes me feel anxious. You only have to read down one paragraph to say 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 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 and everything else we've already seen that 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 on both safety and also on recommendations. Variously four Australians involved with the strategic advisory group of experts on vaccination at the WHO level so a bit of a shameless plug there but it's 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 but doesn't necessarily have a causal relationship with it, so you know you'll see this you you start someone on a on a medicine the next day you know they report a rash started they come back and see you a week later with the rash from the medicine. Well it's often hard to tell. Same with vaccination adverse event of special interests are many of these are events where we often don't know the etiology 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's a certain property to the vaccine so I think something about you know intussusception which is a bowel blockage and rotavirus vaccine well that's an adverse event of special interest, or it just may be that we know that you know serious say events like neurologic conditions are going to cause concern if they occur shortly after a vaccine has been given you know irrespective of of whether they weren't seen in clinical trials or were seen in clinical trials so these are events for which it's appropriate to have ongoing monitoring rapid communication and really careful both some epidemiologic and biologic studies to try and look at causal associations so there's 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'll talk about this a bit more in a minute or the the multi-inflammatory syndrome these sort of vasculopathies that we know the virus itself can cause respiratory distress of course things like an osmium orga you know dermatologic manifestations which have also been seen in COVID-19 itself this is not because we intend to use live vaccines in fact you've heard from kept that there's 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-19 being around they may occur with COVID-19 being around so many countries that where vaccine will be rolled out the virus will be still raging through those communities we anticipate so you'll be seeing COVID infected patients at the same time as COVID vaccinated patients and you know this will be the background really on on which vaccine is delivered.

So what is vaccine-associated enhanced disease? So one of the chatters early on mentioned this, it's really important that when SARS was studied as a vaccine in mice and indeed also in a murine model, sorry a feline model in cats and indeed for one of the MERS candidate vaccines, these are phase, 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 through a few different reasons that can come about because that non-neutralizing 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 cause harm rather than than good so it's 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 to the COVID-19 vaccines and let me tell you that there's 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'm part of a group that occurs late at night every week and public presents on these, and then the second thing is it hasn't been seen so far as hinted in clinical trials nonetheless the safety community really wants to follow this as a potential outcome very closely and studies are being devised around the world to do this, which basically means looking to see if the COVID-19 occurs in people who are vaccinated and if it does is it worse than it would have been if they weren't vaccinated, complicated studies to set up but really really important.

Okay so just quickly through some of the safety data. It's hard to present this in a lot of detail for yet so what what I'll just I'll just go back up here this is the AstraZeneca phase one two data. This is available online and remember this is the viral vectored vaccine. Now the the comparator here wasn't actually placebo, it was meningococcal ACWY vaccine and they gave some people paracetamol and others not and now if you compare that with the actual vaccinated participants and you look up the top to see what I'm actually showing you, chills, fatigue, fever, feverish, headache, joint pain, malaise, muscle ache. Yan can see well, paracetamol firstly didn't make too much of a difference people noticed they had this vaccine more than they 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 yep 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 are lower rates of adverse events in those participants. What about the Pfizer data? Well this is a really busy slide I apologize 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've selected the number two the b2 does candidate which is because it actually had the better safety profile so you might remember Ket showed you the immunogenicity data - there wasn't 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 1 and dose 2 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 favorable safety profile and this is the candidate that's been studied in phase three trials and over here you can see the same types of set up in the the graphs, but here we're 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's still under development with the TGA. It has all the main goals of other vaccine safety systems globally to fully characterize the profile once in use to detect adverse events etc etc and I won't go through all of this but importantly to communicate well I think this is going to be a very important challenge and we'll 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's where everyone I hope is some is participating active surveillance and whilst these are under consideration we we very much hope and expect that the odds fact safety system which I'll 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 will 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'd have to be thinking about vasculitis, these types of things we'd like to know the background rate and of course international linkages and communication plans. So I hope you you are aware of the AusVaxSafety system. It's really easy to find just google search ausvaxsafety.org and these two fabulous tools VaxTracker and SmartVax. And if you jump on the SmartVax website you can actually just join up they can enroll your practice remotely, it's 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 then the results put up on the website and you can follow weekly data there for lots of vaccines, say for example like flu vaccine. We had 300,000 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 week or two before and people will be concerned and I think that's 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'll be causality assessment done, that there are special studies underway which will inform our thinking as these cases are assessed, and to not necessarily you know throw up our hands and panic but to 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 coalface level, you know, just be aware of jumping to conclusions about causality but make sure you report those events on the same, 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's been a lot of focus obviously in R D, purchase and manufacturing partnerships, regulation, and now we're moving into the administration, program design and monitoring and this includes priority groups, I've already mentioned some of this, and there's some challenges in the data that we've talked about. Co-administration Ket's talked about issues with cold chain, the need to ensure two doses and we absolutely will have multi-dose vials so Australia can deal very well with these. We do, we did it for Panvax. There will only be multi-dose vials in the whole of the world for a good period of time because it's not possible to manufacture billions of individual doses, but there'll be you know strong guidance coming out of this and really clear instructions on how to use this. There it always does cause a little bit of of wastage you know and it does pose a bit of a challenge for setting up your clinic so you can minimize wastage of course.

So we think the program will start in quarter 1 2020. That's the plan at the moment, but we don't know which vaccine it'll be yet. They're likely to be other vaccines added in, it's likely that 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've 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 tourists, temporary visas. And the specific clinic so you know I would imagine and I think this is, everybody's talked about this, in the as a very few first doses come online the number of clinics where vaccines 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/ Territory program we know that you know here NSW Health Immunisation, group, you know who are, excellent, will be working closely with you to to step through a lot of where vaccine will go first, and obviously for workplaces where there are these high-risk populations, like hospitals and aged care facilities, it's going to be very important.

Sam: Kristine someone's just pointed out that previous slides should say quarter 1 2021.

Kristine: 2021 exactly what a good idea or we can go back in the time machine and you know not even have the pandemic because we'll have a vaccine already. I love that, maybe that was really wishful thinking, that was the point.

Okay so what can I do to be covered vaccine ready and I think I've even updated this slide but I haven't got the updated version here but you know start to think about your own practice. I would really encourage this. We know vaccines are biologic products, they need enormous amount of respect, there'll 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's incredibly important because you know we don't want to be missing vaccines, not know who's vaccinated, vaccinating someone three or four times. Are you ready with proto because this is a new way of ensuring linkage to the AIR and there's 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 particularly encourage you to go to you know know your public health unit and and how they can help you and of course our 1800 NSWISS NSW Health immunisation specialty service and I apologize that it's not on this slide. Again we'll be needing to be learned about multi-dose vials, cold chain maintenance and this will have to be followed to the t. You know some of these multi-dose vials don't have a preservative because it's not compatible with the vaccine itself, so you know getting your practice ready to to operate in a very slick way can start now in a non-specific way, but really you know, have everybody ready. Accrediting your immunisation nurses, getting you know cold chain monitoring up to date, all of these really critical elements.

So just a couple of take-home messages. In the program's starting soon we don't know which vaccine but we we know which probably basket it will come from, there are many details still to come things to start to get ready there's the 1800 NSWISS number and obviously there's 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 you know 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've already had with controlling the virus and the part you've played in that, so thank you very much everyone.

Sorry I have to end with this because it's a favorite but this tells you how even not more than 200 years ago the public was skeptical of smallpox vaccination that you know people would grow cow parts from from their bodies, now we have eradicated smallpox. I personally think we're 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 we don't you know we don't succumb to any, miss or disinformation like this. Thank you very much everyone.

Sam: That's 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've got one that has come through. Do we know anything let's let's say for the for the leading ones at this stage obviously as you mentioned at the start there is a large number that 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's to be given to pregnant women at all?

Kristine: So at this stage we think there's unlikely to be very little data on pregnant women. We know some women will have become pregnant around the time or may have you know just had conception around the time that they were vaccinated and those women are being followed very closely, but they won't be in really large numbers or enrolled in a prospective controlled way. I'm sure there will be vaccine studies in pregnancy happening more down the track but I think it's important to remember that there are no theoretical concerns, there are no theoretical risks about the platform technologies that we'll be using and pregnant women. So you know some of them will contain adjuvants, now we've 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 you know have been used in in thousands and thousands of pregnant women even though they're not returnedly recommended, so we don't have any express concerns at this stage. There will be limited data and it's going to need to be clinical decision making but of course we need to see what the regulatory advice will be as well and clinical advice.

Sam: Fantastic and there's another one that's 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 won't want to take the vaccine and Kristine I'm sure you'd agree that the answer that that is yes, like with any other vaccine there's going to be people that for their own reasons don't want to take it and as as a GP what you can do is is inform them of of the the risks and the benefits and what the science behind it says and unfortunately that that is all you can do.

Kristine: Look I might want to answer as well but I think 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 alluded to and you know I've got a lot of friends who come up to me and said I won't be having it yet, I won't be having it yet and I say to them, well that's fair enough because we don't know anything about it yet. You know we've still got a lot to learn and we're going to learn it quickly but it's being done in in a rigorous way and I think you know we want to encourage our patients to have questions. There'll be a lot of frequently asked questions we're going to put our own early FAQ up on our own NCRS website, hopefully within the next week to 10 days, just to start to point people to something because people don't like to make decisions when they don't have a lot of information. We'll have a lot of information by the time the vaccines get rolled out. Someone asked why March? You know I mean we don't know yet whether it's March, February or April and you know but but I think it won't be long behind say even somewhere as as you know bold in the way they're making statements like the United States. It's all relative and and these the time frames we're dealing with are incredibly short.

Sam: Absolutely. All righty, 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 that 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's still a lot of unknowns and we definitely don't 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.

Current as at: Monday 30 November 2020
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