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A vaccine – is it possible? And by when? Laureate Professor Peter Doherty

In our 2nd October Special Online Event we heard from Laureate Professor Peter Doherty on vaccines for the Severe Acute Respiratory Syndrome Coronavirus 2 virus (SARS-CoV-2) that is responsible for COVID-19 (the coronavirus disease). Professor Doherty began by pointing the audience to his ‘Setting it Straight’ blog on the Doherty Institute website (https://www.doherty.edu.au/ news-events/setting-it-straight), where he aims to write about 800 words a week. With about 26 episodes under his belt, Peter thinks of these as his weekly sermons and as having stemmed from his Methodist upbringing and lay preacher tendencies! He then progressed to the topic of vaccines, noting that Australia got on to the research and development of vaccines ‘fast and well’. The Chinese published the gene sequence of the virus in mid-January, very shortly after they had isolated the virus. Once the gene sequence was published, that was all the information needed by vaccine developers to get on with making vaccines. Australia reported its first case of COVID-19 on 24thJanuary 2020. Fortunately, the returning traveller had been very responsible and had selfreported before presenting and being admitted to the Monash Medical Clinic. Scientists at the Doherty Institute gained a sample from this patient and after isolating the virus were the first to supply the infectious virus to other scientists around the world. This was a very important first step for vaccine development for a number of reasons. Firstly, scientists need the infectious virus to do virus neutralisation tests that detect the presence in the blood of antibodies that prevent the infectivity of the virus. These virus neutralisation tests are the ‘gold standard’ of measuring antibodies in a virus infection. (Various molecular surrogate tests have been developed since.) A live virus is also the ‘gold standard’ for virus challenge studies in animals, a usual part of the vaccine testing regime. The animals with COVID-19 that are particularly useful for vaccine evaluation include genetically modified mice that have the ACE-2 (Angiotensin Converting Enzyme 2) molecule – the molecule with which the virus binds to get into the cell. The Walter and Eliza Hall Institute of Medical Research (WEHI) have had these mice for some time. Scientists at the Doherty Institute have had some access to the PC3 (Prostate Cancer Cell Line) level mouse facility at the WEHI for virus challenge studies, using a natural variant of the SARS-CoV-2 virus that binds ACE-2 to the mouse, and are currently developing another collaboration in Melbourne that will allow them to do more extensive animal studies with live virus. Another animal that is particularly useful is the hamster. Australia had not previously used these desert-dwelling animals because, if released accidentally into the wild, they would multiply quickly (like rabbits) and have devastating effects on the native fauna and flora. However, a facility in the United States has now been identified for virus challenge studies in vaccinated hamsters. The Doherty Institute now has two vaccines under development, one further ahead than the other. The Institute has also been undertaking a lot of testing to help CSL and the University of Queensland with their novel vaccine being made under the umbrella of the Coalition for Epidemic Preparedness Innovations (CEPI). CEPI was cofunded by the Bill and Melinda Gates Foundation, The Wellcome Trust and a consortium of nations, and launched formally at the World Economic Forum in 2017. The Chair of CEPI is Jane Halton, National COVID-19 Coordination Commissioner and, previously, Secretary of the Australian government’s Health and Finance departments. CEPI endeavours to develop vaccine platforms that can be deployed in global emergencies. Gavi, the Vaccine Alliance, and the World Health

Organization are also involved in the global collaboration to accelerate the development, production and equitable access for every country in the world to COVID-19 tests, treatments and vaccines. To make vaccines in the ‘old days’, one approach was to grow the virus up and then kill it (the approach still used for the influenza vaccines). Another approach was to attenuate the virus by passaging it repeatedly through cell cultures or animals, and thus gaining genetic mutations of the virus that were progressively weaker and thus less virulent for humans. With reference to poliomyelitis, Professor Doherty explained further these two approaches. The Salk vaccine (developed in the 1950s by Jonas Salk) was a typical example of a vaccine developed in the older style whereby ‘buckets’ of the virus were grown up and then killed. The vaccine holding this killed virus was then given by injection. If the killing stage is done properly, this is a safe vaccine. Unfortunately, however, there was a breakdown in this approach at the US-based Cutter Institute. The so-called ‘Cutter Incident’ involved the failure to inactivate (kill) completely the polio vaccine licensed for use in the United States – meaning that people were injected with live polio – and the resulting epidemic of iatrogenic paralytic polio. Obviously, this cannot happen again. The Sabin vaccine is an example of an attenuated vaccine. The poliovirus was passed over and over in tissue cultures to keep it alive but in a weakened state. People took this vaccine on a sugar cube. The world is near the point of eradicating polio worldwide, and thus this vaccine is not right for use to achieve this end state. This is because the weakened virus grows a little in the cells (usually the gut) and may thus revert to virulence. A live virus can thus be produced in one person, defaecated and passed on to others – obviously, not the aim for total annihilation of the poliovirus. Pakistan and Afghanistan are the only countries where polio has not been eradicated. This is partly because of conflict situations and partly because those developing or delivering the vaccine were killed following propaganda that the vaccination teams were being used to spy on people. Returning to the topic of a SARS-CoV-2 vaccine, Professor Doherty expressed his understanding that there has been a ‘killed virus’ vaccine given to some military in China and that there is at least one ‘attenuated virus’ vaccine under development. These vaccines tend to have a long development time. Several other and different types of vaccines are also in the development pipeline. All are dedicated primarily to the development of an antibody response. To understand what is meant by the ‘antibody response’, Professor Doherty suggests going to his ‘Setting it Straight’ site where he has a few blogs giving user-friendly and simple-to-follow explanations (see link above in second paragraph of this article). He also explained this response during the presentation. When infected with a virus we get T-Cell and B-Cell responses. T-Cells and B-Cells are different classes of lymphocytes that recognise (through very, very specific receptors) something on the virus and then multiply again and again (dividing every six hours) to generate quickly an enormous number of lymphocytes. B-cells make the antibodies – they differentiate into plasma cells that secrete the antibody proteins into the blood, lymph or any other body fluid. These antibodies then float around in the body fluid and, in the case of SARS-CoV-2, including hopefully in the nose mucus. If the antibodies encounter the virus or the particular bit of the virus for which they have specific receptors, they will ‘grab hold of it’ and they can block the virus from infecting or label it for destruction by various other body mechanisms. Acknowledging that this process sounded complicated, Professor Doherty reassured us that immunology is the most complicated subject! All viruses are obligate intracellular parasites. This means that they lack metabolic machinery of their own to generate energy or to synthesise proteins. They thus depend on host cells to carry out these vital functions. Antibodies are basically molecules floating around in our body fluids that grab hold of the virus and either stop it from getting into the cell where it has to go to multiply; or attach to the virus and, in doing so, make the virus a target for destruction through such mechanisms as phagocytosis (ingestion; engulfment), endocytosis (dragged into the cell, chopped up and bathed in acid) or attach it to a complement cascade (a biochemical process that helps the immune system cells to eliminate the invading virus by ‘blowing holes in things’). Another component of the immune response is the T-Cell response, which is what Professor

Doherty worked on throughout his career. Killer codes for the spike protein on the surface of the T-Cells are the ‘assassins’ of the immune system. SARS-CoV-2 virus is then put into this disabled They travel around the body and kill off damaged adenovirus, which is then grown up for vaccine or abnormal cells (and for this reason are being production in a ‘packaging cell line’ containing used in new cancer therapies). They also ‘bump adenovirus genes that allow the disabled virus to off’ virus-infected cells and virus particles. They be produced in quantity. When given as a vaccine, are not the ideal vaccine candidate because once the disabled virus then goes through a partial the immune response has settled down after a growth cycle in human cells, so that virus proteins first infection or vaccination there is a return to are produced but no infectious progeny are made. a resting state. The T-Cell response would thus need to be restimulated. Notwithstanding this need for restimulation, some programs (e.g., those developing new RNA vaccines) are testing products that will prime both T cell and B cell responses. The spike protein is the protein that attaches to a molecule called ACE-2 on our cells and it is what allows it to get into our cells and start to multiply. Many vaccines are directed very specifically at the receptor binding domain (RBD) on this spike protein. To date, though there have been some There are five vaccines in the well-funded mutations of the SARS-COV-2 virus, none of American Operation Warp Speed initiative. This these have seriously affected the RBD on the initiative has the goal of producing and delivering spike protein in a way that antibodies against it 300 million doses of safe and effective vaccines by do not neutralise it or block it. To grow the virus January 2021. up to make the vaccine to make it fully infectious, One of these five is the Jenner AstraZeneca vaccine being developed by the Jenner Institute and the Oxford Vaccine Group at the University of Oxford and AstraZeneca, a BritishSwedish multinational pharmaceutical and biopharmaceutical company. Australia has signed it must be grown in a cell line that has adenovirus components. Some objections to this vaccine have been raised by the Anglican Archbishop of Sydney because the cell line developed at the Wistar Institute in Philadelphia over 30 year ago originates from a medically aborted foetus. up for this vaccine and CSL has agreed that they There are a number of other genetically modified can make this vaccine. ‘fake spike protein’ vaccines being developed based on human adenoviruses. The aim with these vaccines is to train our bodies to detect and end any real SARS-CoV-2 infections. These adenovirusbased vaccines use adenovirus25 (Ad25), Ad26 and Ad5. At least one of the Warp Speed vaccines is an Ad5 vaccine that is being tested in the United States. The Russian

Source: Funk, C.D., Laferrière, C. and Ardakani, A. (2020). A Snapshot of the Global Race for Sputnik V vaccine is

Vaccines Targeting SARS-CoV-2 and the COVID-19 Pandemic. Frontiers in Pharmacology, 19 June, https://doi.org/10.3389/fphar.2020.00937 based on two adenovirus vectors (Ad5 and Ad26), The Jenner AstraZeneca vaccine is a chimp modified with the SARS-CoV-2 spike protein. adenovirus vectored vaccine. This approach has There are also protein vaccines like those being been used previously in various experimental developed by the University of Queensland strategies but has not led to a commercially (UQ) using their proprietary ‘molecular clamp’ produced vaccine. The adenovirus is disabled technology. As explained previously, the SARSso that it cannot go through a full growth cycle CoV-2 virus enters a host cell. Prior to this entry, and make new infectious progeny. The gene that the spike proteins are referred to as being in a

prefusion native virus surface form. After the virus becomes enveloped within the host cells, it drives fusion of the virus and host cell membranes; and the spike proteins are then less stable, change shape and are not recognised efficiently by the immune system. The UQ technology thus aims to lock the stable prefusion version of the surface spike proteins in their native virus surface form and to grow these in huge vats under GMP (Good Manufacturing Practice – extremely high-quality and safe conditions and standards). CSL has the capacity to make at least 100 million doses of the adenovirus vaccine or the UQ vaccine annually at its plant in Broadmeadows. These might be the vaccines that Australians will get, possibly from about the middle of 2021, if all goes well with the trials. Though the UQ vaccine is behind in the trial schedule it looks good so far in the animal studies, with, for example, hamsters administered with this molecular clamp vaccine demonstrating a neutralising immune response that was better than the average level of antibodies found in patients who had recovered from COVID-19. CSL has a strategy in place to advance this vaccine into Phase III clinical trials in 28,000 people later this year in the United States. The vaccines that are currently in Phase III clinical trials in the United States include the Jenner AstraZeneca clinical trial (though this is currently on hold in the US, perhaps because of a problem in the control group, it is continuing in the UK and Brazil). Another vaccine (a DNA product) is also on hold, but this is probably to do with the virus administration system (electroporation), rather than any safety concerns about the vaccine product. There are also a couple of mRNA vaccines comprising self-amplifying nucleic acid encoding for the SARS-CoV-2 spike protein – that is, just the genetic material of the spike protein is administered. These vaccines look to be good so far. About 30,000 people are involved in each of these Phase III trials on a two-for-one basis – that is, two are given the vaccine and one is given a placebo. Where possible, all vaccines are being tested in older people who are more likely to develop obvious symptoms. To date, these mRNA vaccines look to be making very good antibodies in older people. We may hear some results in October (if they decide to tell us) about how well at least one of the vaccines is working to prevent symptomatic disease, and it is possible that some of these vaccines could be rolled out as early as the first quarter of next year due largely to $1B funding given to each of the ‘Warp Speed’ companies to proceed with vaccine production. Clearly, no vaccines will be deployed before FDA approval, which will require data for at least some individuals assessed two months after getting the last dose of vaccine, and the evaluation of those results will likely take another one to two months. Some of these vaccines have, however, been on trial at some level since July. How they will be used is being actively considered, and it is impossible to be too prescriptive before results are in. There are thus a number of very encouraging signs that we shall have vaccine success. We know that human beings can make antibodies to these vaccines and they look good. We know that we can protect animals from severe lung disease following challenge with the SARS-CoV-2 virus in challenge animals of choice – hamsters and ferrets, and nonhuman primates (African green monkeys, rhesus macaques) – and with no vaccination danger signals. However, we still do not know what happens when a vaccinated human being gets infected – that is, how well the vaccine protects them from the virus and from developing the COVID-19 disease. Hence, about 150,000 people are being tested (given the trial vaccines) in areas of the United States where there is a high incidence of the SARSCoV-2 virus. Many other people are also being tested in high-incidence areas in Brazil, South Africa and various other countries How well these vaccines will work is, of course, another unanswered question. With the influenza vaccines, we know that they are only 40-60% effective. This is the great challenge. Globally, the only respiratory virus vaccine made and deployed for adults is the influenza virus vaccine. We also make the respiratory syncytial virus (RSV) for infants, but that is not normally given to older people. Influenza vaccines for adults are thus not the greatest vaccines. We have wonderful vaccines against measles and polio because these are systemic diseases. When these viruses get into the body, they multiply first in epithelia in the nose and/or the oropharyngeal area. Symptoms then result as a consequence of that locally produced virus being disseminated in the blood. In measles this is evidenced by the skin spots. However, the virus can also go into your ears, your lungs and your brain (with about 1 in every 1,000 infected children in less-developed

countries dying from encephalitis). Similarly, polio gets into the blood and thence, in some, into the spinal cord, killing large motor nerve cells and causing muscle paralysis as a consequence. Systemic vaccines against these viruses are thus very effective because these viruses do not change very much and it is comparatively easy to maintain reasonably high levels of neutralising antibody in the blood. The COVID-19 disease has a respiratory element, with, for example, shortness of breath and lung infection leading to pneumonia. It also has systemic components. The virus can get into the heart and kidneys, and into blood vessel walls, causing severe blood clotting problems (coagulopathy). Cytokine storms are also seen – like those in severe influenza – whereby large amounts of pro-inflammatory cytokines are released, and the inflammatory reaction becomes excessive. Though there are parallels with influenza, the SARS-CoV-2 virus is thus a very different infection with a different pathogenesis (chain of events leading to the disease and development of the clinical disease). It would be ideal if the vaccines would work more like the systemic vaccines during, particularly, the systemic phase of the disease. In addition to later-stage pneumonia, these systemic disease components tend to be what is leading to death or severe disability (e.g., following a stroke). The more people who take the vaccine, the better, as this will bring the world closer to the stage of ‘herd immunity’ – the resistance to the spread of the virus in a population that results if a sufficiently high proportion of individuals are immune to the disease. Achieving herd immunity naturally is likely to require that at least 60-70% of people have been infected and have made antibody, a situation that is not yet likely to have occurred anywhere except in very localised regions, and certainly not across any country. Looking, for example, at the United Kingdom, though there are 7,000 new cases and 70 deaths a day (a 1% death rate), this is not near herd immunity levels. Brazil has seen about 40% of its population infected in some regions but this is well below the minimal 60% infection rate required for some herd immunity. No country or region is near herd immunity. Vaccine uptake is thus imperative. In response to a question about mutations, Professor Doherty reiterated that the mutation rate for the SARS-CoV-2 virus was not high. Like influenza and HIV, SARS-CoV-2 is an RNA virus – that is, it has RNA (ribonucleic acid) as its genetic material and has a smaller genome, usually encoding only a few proteins. HIV is about a third, and influenza a bit less than half, the size of the SARS-CoV-2 virus. Neither HIV nor influenza has a mini-proofreading mechanism. Both thus throw off mutants often and at an enormous rate. With HIV, this proliferation of mutants in an infected human being has thus made it so difficult to find a vaccine. Globally each year also, the influenza virus throws out millions of mutants but only one of these emerges every year or so to cause a seasonal influenza epidemic. The SARS-CoV-2 virus does not mutate at the same high rates. Researchers at the Microbiological Diagnostic Unit Public Health Laboratory at the Doherty Institute, led by Professor Ben Howden, have pivoted from the sequencing of bacteria to the sequencing of this virus and are now responsible for the sequencing of about 60% of the Victorian SARS-CoV-2 isolates. Such sequencing is the basis for genomic epidemiology whereby known virus mutations have been ‘bar coded’ (according to clades and subclades – strains/sub-strains) and used to track the origins of the virus. For example, genome sequencing and matching to the genome type called clade 20C have suggested that a high number of the current Victorian cases stemmed from one Rydges on Swanston hotel quarantine case. Encouragingly also, though there has been a bit of mutation in the RBD (receptor binding domain), the antibodies are still working against this virus. Mutation can often be associated with a ‘fitness cost’, meaning that a variant strain may not replicate as well as the original non-mutated virus in a naïve population (which is what most of us are) and are thus not able to take over. Mutated viruses may thus, in the main, tend to burn out. With respect to a question about antibodies floating in body fluids and randomly bumping into and latching onto the virus, Professor Doherty explained that there are a variety of delivery systems. The vaccine will likely be injected into the arm. However, it could be inhaled up or puffed into the nose, swallowed in pill form, or administered through a skin patch. Whatever the delivery mechanism, the vaccine material then gets into the lymph system which drains to the lymph nodes where the immune response is stimulated. For example, injection of the vaccine into an upper

arm muscle will result in the vaccine going into the lymph nodes under the arm and the generation of a dynamic immune response in these nodes, and thus a bit of swelling and pain under the arm. After about five to ten days, the antibodies that are produced are secreted from the lymph system into the blood and then yes, they may ‘bump into’ the virus if the person has been infected. There is no ‘dating agency’ for the antibody to meet the virus. It is thus obviously important for the body to generate enough circulating antibody so that the chances of encountering the virus are increased. The more antibody you have in the blood the more protected you are. It is possible that the immunity provided by the vaccine will not be long-lived. We do know that some who have had the disease have been reinfected, and it’s likely that there will be some virus replication in, at least, the nose in those who have been vaccinated, a situation that would provide a natural boost to the vaccine response. In fact, the vaccine will likely be delivered in a prime boost mode with probably two shots (of the same or different vaccines). The first will stimulate the immune response and the production of SARSCoV-2 antibodies. The second would then serve to drive the level of these specific antibodies up to increase the probability of encountering and combatting the virus if reinfected. The frequency for these boosts is not yet known but it may need to be every year or so. In response to a question about the lower impact of the SARS-CoV-2 virus (unlike measles and polio) on children, Professor Doherty spoke first to the pattern with influenza noting that young children who have never had the flu are very susceptible to influenza and will, indeed, often bring the virus into the household. In contrast, with SARS-CoV-2 virus, the children are not normally bringing it into the household and are generally the last to be infected when the whole household is infected. Though there have been some cases of very severe infections and deaths in children, the incidence of the clinical disease has been very, very low. One reason for this lower incidence is that an early form of the antibody response – a molecule called IGM (Immunoglobulin M) – may be better in children and thus provide enhanced protection. Another is that the blood clotting cascade (microcoagulation) that has been leading to strokes and clots in adults, matures in adulthood (in the 20s) and may thus be very different and have far less clinical impact for children. In response to a question about the success of a vaccine for people who have compromised lymph systems (e.g., through surgical removal), Professor Doherty suggested asking the vaccinator to deliver the vaccine near an area of healthy lymph nodes. For example, if lymph nodes had been removed under one arm, the injection could be given on the other arm. In response to a question about the certainty of the results from SARS-CoV-2 virus tests, Professor Doherty indicated that yes, there are some false negatives and some false positives, but, on the whole, the PCR (polymerase chain reaction) test used in Australia is very sensitive and considered the ‘gold standard’ for diagnosis of COVID-19. There are a lot of other tests coming into the market that are not quite as sensitive but with lower processing times, that might prove useful for community testing, especially in high incidence areas. In response to a question about which of the vaccines in trials would most likely succeed, Professor Doherty indicated that we will all have to await the results (if announced). In total, he knew of about 17 vaccines in Phase III clinical trials. The United States has some of the best vaccine development systems in the world and it has allocated $1B to each of five candidates under Operation Warp Speed – thus indicating, also, their uncertainty as to which candidate would be successful. The Chinese have also been testing candidates in their military, and possibly also in Indonesia and the Middle East. Russia was also progressing a vaccine fast. The UQ vaccine was outside Operation Warp Speed. As mentioned previously, these new mRNA vaccines have not previously been deployed, however the pre-Phase III results have been very encouraging. In response to a question about whether or not the development of a vaccine is a gamble and that we might thus have to learn to live with the virus and under governments making appropriate arrangements, Professor Doherty suggested that it is unlikely that vaccines will bring this pandemic totally to an end. However, with a high vaccination rate it is very likely that they will bring us to herd immunity levels. If we can use the vaccine to get up to 60-70% or more of the population with specific antibodies, we should be able to bring the risks from this virus, as well as its ability to spread, right down. At the same time, Professor Doherty mentioned that we are getting better at treating the clinical disease. Those who are

dying now, more frequently have had a number (around four) of comorbidities. About half the people who would have died months ago, are now surviving because of these medical treatment and care improvements. For example, doctors are administering low-dose heparin to counter coagulation, Remdesivir as a broad-spectrum antiviral, dexamethasone to counter excessive inflammation and, as we heard recently, President Trump has been given a cocktail of monoclonal antibodies. Administration of these medications earlier in the clinical disease has also proved to be beneficial. With a combination of vaccination, better medical treatment and better drugs it should be possible thus to live with and manage this disease without repeated shutdowns. It is not normal to shut down the world because of an infection. The reality for many countries has been, however, that shutdowns have been necessary because the hospital system would otherwise have become overwhelmed because of the huge caseloads, those at the front line would also become infected, more younger people (particularly in this workforce and as seen in the early cases in Wuhan) would die and the whole health system would collapse. Professor Doherty suggests that once this pandemic has settled, it will be important to undertake a thorough and objective forensic review from all perspectives – sociological, economic, public health, science, travel, etc. – and to determine criteria-based local and global responses. For example, in preparation for a future and similarly infectious and devastating epidemic, it will be important to gain a global agreement that flights to and from the country with an initial outbreak should be shut off immediately. While previously, and in the influenza community, there had been a ‘mantra’ to not stop the planes because of the flu, Professor Doherty felt that the experience of New Zealand and Australia through closure of their borders demonstrated the success of this strategy, particularly when compared to countries of similar populations that had not restricted travel. In response to a question about potential political influences on vaccine development – for example, in the United States with Operation Warp Speed – Professor Doherty explained that there are two major ‘check and balance’ factors in the United States. Firstly, the FDA (the US Food and Drug Administration agency responsible for protecting the public health by ensuring safety, efficacy and security) will only support a vaccine that is at least 50% effective in preventing the disease. Secondly, any vaccine manufacturers must bring the vaccine to the FDA for approval. All nine of these manufacturers in the US have indicated that they will not bring their vaccines to the FDA until they have confirmed the vaccine to be safe and efficacious. In Australia, our federal and state politicians are doing well, and Professor Doherty welcomes the cessation of the blame game and focus on the lessons to be learnt. In response to a two-part question about whether the SARS-CoV-2 virus was an old virus and about the features that make it so virulent, Professor Doherty explained that yes, it is an old virus in bats. Though it was known that blood-sucking bats could carry and transmit rhabdoviruses (rabies-like viruses), it was not until the 1990s that immunologists realised that there were other bat viruses that could be transmitted to humans and other animals. The Hendra virus infects large fruit bats and may be passed on to horses and thence humans. The Nipah virus (predominantly in Malaysia) is hosted also in fruit bats and transmitted to humans via pigs. Filoviruses – such as the Ebola virus and the Marburg virus – are now known to be bat-borne viruses. Three coronaviruses have come from bats over the last 20 years – the first SARS virus, the MERS (Middle East respiratory syndrome coronavirus which is still circulating and much more lethal) and now SARS-CoV-2. These viruses have evolved to be in bats and there is something about the bat immune system that allow the viruses to persist. The bat immune system emphasises responses that are different to those emphasised in the human system where there is a greater tendency for cytokine storms. The virulence is particularly high in the elderly, and this has been manifested by severe clinical disease and more deaths. However, we are yet to understand the longer-term effects of the disease across all age groups, and there are thus now many longitudinal studies being undertaken to tease these out. In response to a question about his ultimate goal for medicine in humankind, Professor Doherty spoke, in the first instance, to protecting the young and ensuring greater survival rates for children, mentioning that the world still loses half a million children each year from malaria. He sees childhood vaccines as particularly important.

With the elderly, he noted that we have people living a lot longer (and not generally dying from an infectious disease until this SARS-CoV-2 virus came along) and facing such conditions as degenerative diseases and Alzheimer’s disease. Medicines and other therapies in this domain are thus of interest. Another area of enormous importance and often under-addressed is medical care for women. In response to a question about the quality of international collaboration to develop the vaccine, Professor Doherty expressed great satisfaction in the collaboration between medical researchers and the pharmaceutical companies. He gave the example of a company in Colorado coming forward to test the Doherty Institute vaccine enhancers. He noted also that there had been improvements in information exchange and sharing. Previously, results would not become evident until published in a peer-reviewed, high standard journal. Of late, medical researchers had been adopting the approach used in the field of physics whereby pre-prints are circulated for commentary before publication. Though many of these pre-prints on vaccine development might not make it through the subsequent peer-review process, the shared data and views have nevertheless led to robust discussion, the incredibly quick dissemination of good results and transparency. Professor Doherty explained also that the reason why he is spending time on public health talks such as this was to take the burden off the many scientists at the Doherty Institute who are working incredibly long hours on and in international committees, conferences and scientific networks that operate across a variety of time zones. In response to a question about the lower rate of deaths and hospitalisation in the second wave in Europe, Professor Doherty noted that this was likely in part because older people had learnt to keep themselves apart and not exposed to the virus, and that the virus was thus most likely infecting a younger cohort with less comorbidities and a lower incidence of severe clinical disease. The other reason is that treatment of the symptomatic disease has improved (anticoagulants, dexamethasone, Remdesivir, etc.). In Australia, Professor Doherty mentioned that we could not wish for a better response from all levels of government – federal, state, local – in terms of supporting the science. Yes, there have been policy failures, especially with respect to aged care and hotel quarantine. However, his view was that these are problems in Australia’s structure, particularly in relation to silos. Overall, the response has been excellent and particularly when compared to the rest of the world. In response to a question about disturbing sideeffects experienced by those who have recovered and the potential for the vaccine to attenuate these side-effects, Professor Doherty expressed his particular concern about these long-term sequelae. Though there are many anecdotal reports, the results from systematic studies are not yet available. This is a huge data gathering exercise and one that is being undertaken by a number of institutes. For example, the Doherty Institute is following up with all those who became infected, especially those who were hospitalised and released. Imperial College in London has a widely distributed App that has millions of infected and previously infected people signed on to report any later symptoms. There are also a number of studies being reported through The Lancet, a weekly peer-reviewed general medical journal. Some people have had severe damage to their hearts (cardiomyopathy) which may be permanent. This means that the virus can get into the heart, that it can grow in the heart and that it can kill heart cells. Other longer-term problems appear to be resulting from clots. While with influenza, the key cause of death with virus infection of the lungs was anoxia (the inflammation causing the alveoli to fill up with fluids that blocked gas exchange – a drowning), another problem with the SARSCoV-2 virus is micro-clots in the capillaries (small blood vessels) of the alveoli (small air sacs), again affecting gas exchange, but also bringing the risks of clots breaking off and travelling further through the blood to become blocked and thus lead to a lack of blood supply beyond the blockage (e.g., leading to a stroke or heart attack). The President of The Graduate Union, The Hon Diana Bryant AO QC, gave a closing address to thank Professor Doherty for his clear and articulate explanations of the complex and wide-ranging field of vaccine development. She extended gratitude also to the audience for their excellent questions, the answers to which from Professor Doherty were equally enlightening. Thanks were also extended to the wonderful team at the Doherty Institute, as well as to the international scientific, medical and public health community.