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Lecture 1: "COVID-19 and the pandemic"

Jun 08, 2021
hello everyone, we are about nine months into the

covid

pandemic

in that time a remarkable amount of information has been learned about the novel coronavirus and host cell biology immunology epidemiology and clinical disease there are complexities to these issues that confuse even the experts the purpose of this course is to learn what we know about these topics from the world's top scientists i'm richard young and along with fukundo batista and our teaching assistant linda feyen we are core professors for mit's 700 course on covet 19 sars kobe 2 and the

pandemic

I'm going to make some comments to the students who are registered for this course and then I'll introduce our first student speakers.
lecture 1 covid 19 and the pandemic
If you forget any of the following instructions, you can find them on the course website. Live first attendance at

lecture

s is encouraged but not required recordings of

lecture

s will be posted with a link on the canvas site su ta lena will post a notice after the lecture as a survey on canv as a response to which will be required before the start of next week's lecture, responses will be graded for participation, and students must participate in at least 90 percent of these prompts to pass the class. Lenna will hold a session on Mondays from 1 p.m. m. to 2 p.m. m.
lecture 1 covid 19 and the pandemic

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lecture 1 covid 19 and the pandemic...

Except on holidays, review relevant background material to help you better understand the next day's reading. Recommended readings and other reading materials are posted on the Canvas site and will be suggested along with the prompts. students can submit questions via the qa feature and the zoom webinar. Selected questions will be discussed at the end of the lecture and students are welcome to ask any unanswered questions during office hours. Our first speaker for this course is Dr. Bruce Walker. Dr. Walker is a medical scientist. and immunologist, founding director of the reagan institute of mgh mit and harvard howard hughes medical i institute professor of medicine at harvard medical school and professor of the practice of medicine at mit is also an adjunct professor of medicine at the medical school nelson mandela at the hometown kuala zulu university in durban south africa where he has catalyzed the creation of two major research institutes dr walker is one of my scientific heroes a person who has played a major role in tackling the AIDS pandemic and who now helping us tackle the coveted pandemic last week he and his collaborators published a major story in the wild showing that t cells in some people can apparently cure hiv infection along with arlene sharp is co-director of the massachusetts consortium recently established on pathogen preparation a collaboration between more than 500 local scientists focused on research harvard covet 19 mit bu tufts umass and the academic teaching hospitals in boston bruce thank you very much for giving the first lecture in our cou Well rick thank you very much I am happy to do this as rick indicated I am a physician scientist, I graduated medical school in 1980, I came to Mass General with the intention of becoming a family doctor, but then something very strange. it just so happened that it was the emergence of a new disease none of us knew what it was the people who had it were dying left and right we had no treatments and it became clear to me very quickly that if we didn't learn as frontline doctors from our patients we would see people die So I went the route of taking care of patients and doing scientific research and I've continued to work on HIV throughout my career and in January of this year to put This is my perspective on it.
lecture 1 covid 19 and the pandemic
I was teaching a course for MIT and Harvard undergraduates in Kwazulu-natal, South Africa called the evolution of an epidemic, and this is a course that uses HIV as a model to try to understand how an epidemic arises. clues to p Patients guide scientific discovery and how policy and advocacy influence the course of an epidemic now, by chance one of the things we did was visit traditional healers and by chance one of the people in the course was a mit student who had just returned from wuhan and another was gilead's director of emerging pathogens a former trainee of mine i had invited as one of the speakers the student from wuhan started receiving text messages several times a day from his family talking about what a desperate situation was there related to this new um this new pneumonia that was coming up and diana brainard the gilead person was getting phone calls every day from doctors in china asking her to release a drug they had developed for ebola called remdessevier so they could could test it to see if it had any effect on this deadly new pathogen.
lecture 1 covid 19 and the pandemic
It was clear to me from those conversations that this had the potential to be a big problem, um, as rick said, I'm the director of the reagan institute, our mission is to harness the immune system to prevent a cure for human disease with a focus in infectious pathogens of global importance and our strategy is really to use interdisciplinary disciplines. collaboration along with flexible funding to try to make progress and we're fortunate to be embedded in one of the best biomedical research ecosystems anywhere so we started working on this right away and what I'd like to do now as the first speaker is to give you a little bit of an overview of what we know how this pandemic started how the sars cov2 virus causes the disease what are the prospects for treatment and what are the prospects for vaccines so let's get into this let's put in the perspective of what we experience with hiv so hiv was recognized in 1981 but the infection began to be transmitted in the united states at least in 1978 or even earlier so in 1981 it was c i knew something was going on was 83 two years later before we knew what was causing this new disease and it took two more years to develop a diagnostic test so we could really know who I had it.
Now let's compare what happened with this particular pandemic so that what happened was that patients started arriving at hospitals in wuhan with pneumonia of unknown cause and looking back it was late December when this cluster of cases happened. and there was a really important observation made by the health care workers and that was that these people had a common experience of being in this hunan market, which suggests that it could be a transmissible agent that led to the use of shotgun sequences to identify the ideological agent and to the development of a pcr-based diagnostic test that everything that took four years for hiv occurred in less than a month, making it an extraordinary tribute to the advances that have been made in science Over the years, sequencing allowed scientists to recognize this as a beta corona virus, which is an RNA virus that has a single RNA strand and then u an outer envelope with a predominant spike protein which is an important target for immune response uh the origin of the virus is almost certainly from bats originally it is also closely related to coronavirus it has been identified in pangolins but it is likely that transmission has passed from bat to pangolin and then to humans, although the epidemiology is not yet certain in that regard. not the first pathogenic human coronavirus we have seen sars in 2003 caused a total of 8,000 cases with a fatality rate of 11 but luckily the transmissibility of sars was not that high mers arrived in 2011 and still persists there have been 2,500 more some cases with a much higher case fatality rate of 34 but again thankfully low transmissibility but look at the contrast to sars kobe 2 now we have 25 million out of 25 million cases as of this morning the estimated fatality rate is between one-half and one percent, but it varies widely by age group and geography, and is highly contagious.
I think the important thing for everyone to recognize from this slide is that we can expect we have additional coronaviruses in our future and the great fear and I think what is an existential threat to humanity is the possibility of a coronavirus with the transmissibility of sars kobe 2 and the case fatality rate of mers, so it really behooves us to monitor these emerging pathogens. Why has sars kobe 2 spread so effectively? This is largely because transmissibility begins before symptom onset, and indeed this is very different to mers and sars, which are only at their peak of transmissibility a number of days after symptom onset, this makes it very difficult to do case tracking and isolate infectious individuals, not surprisingly we have a major pandemic 25 million global cases uh 850,000 deaths and over 6 million infections in the US, which it's uh the most effective country in the world so how come sars kobe 2 cause disease um i would like to start because of the diverse audience with just a basic concept to understand what is the difference between a virus and a bacteria looking here uh e coli compared to sargeras movie 2 size i have exaggerated the size of the virus here compared to the bacteria but there are significant differences between these Two, um e coli has four more than four thousand genes, like other bacteria, it is metabolically active and capable of reproducing independently. sars kobe 2, on the other hand, has a total of 10 genes and 14 open reading frames, is metabolically inert, and cannot reproduce. regardless, instead it depends on the ability to infect the human host and to command the human host to actually make the genes that are normally making proteins for the cell to use for its own purposes to hijack that and force the cell to make viral proteins so the virus can replicate and make new copies of itself um when it was identified that the initial infections uh were in the lungs they immediately focused doctors on getting specimens and trying to find the ideological agent which is what happened to through sequencing of long epithelial cells and that also led to a search to understand how the virus actually entered those cells and that led to the identification of ace2 as the receptor there was an advantage to this because this is the same receptor that the original sars coronavirus which isn't the um though, those aren't the only cells that get infected, cells the goblet and hair cells in the nose are quite infectable and that actually uh probably facilitates uh transmission lung pneumocytes are infectable that's how we get pneumonia the gut is also infectable resulting in diarrhea in som People, the virus can infect too circulating endothelial cells and this leads to what is believed to lead to coagulopathy and coagulation resulting in a great deal of morbidity.
Cardiac myocytes can also express the receptor for more this coronavirus and myocarditis has been another disease. that has been noticed and it even seems possible that cells of the central nervous system can also become infected, such as olfactory neurons, this infection does not occur without the body noticing and one of the ways in which the body defends itself is that the cells b one arm of the immune response begins to produce antibodies, which are proteins that bind directly to the virus; are generated in response to the virus; they learn in the lymph nodes how to recognize it effectively and then attack and destroy it if, however, the cells become infected, then another arm of the immune system kicks in, the so-called killer cells or cytotoxic T cells, these recognize the infected cells because once a cell is infected, it alerts the body to the fact that something bad is going on inside that cell by presenting viral peptides on the cell surface in conjunction with an hla class 1 molecule a surface receptor on these cells foreign peptide in the hla molecule in the junctional groove alerts these killer cells to the fact that something bad is going on, they recognize it and deal a lethal blow to the cell killing it and thus eliminating the infectious virus so that's okay, we have these immune responses that are being generated for this virus in the same way that they are for other viruses, why aren't they doing a better job?
Well, it turns out that the production of antibodies from the b cells is affected and this is work that is the work of ship pillai, who will speak later in this course where he pointed out through autopsy studies that, in fact, unlike a normal immune response, is generated within a lymph node where these germinal centers result in affinity maturation of antibody maturation that allows for recognition of what happens in

covid

19 disease is that these terminal centers are not formed , so there is an abnormal immune response going on that we are all trying to better understand, let me now introduce a second concept and that is to make sure that we understand thedifference between infection and inflammation, infection is the invasion of the body by disease-causing agents, their multiplication in the body, and then the reaction of the host tissues to that pathogen, inflammation, on the other hand, is the process of fighting the body against things that harm it, like infections, by releasing chemicals that are also called cytokines that activate the immune system and recruit other cells, so the second reason the immune system doesn't do a better job is because it seems like you're Killer cells are ineffective at killing infected cells, but they do produce many cytokines.
These chemical messengers are released in the same way as infected cells. chemical messengers these then act on other cells and activate them to cause even more chemical messengers and all this immune activation leads to problems in bystanders and leads to this hyperimmune state which has been called an inflammatory storm or a cytokine storm and here looking at a normal lung on the left you can see that the alveolar air sacs, which is where the gas exchange between breathing in and taking oxygen into the bloodstream happens, you can see that those are very thin membranes that allow easy passage on the right, you see what happens in covid19 disease there is this massive infiltration of inflammatory cells marked thickening of the septa and impaired gas exchange leading to the clinical problems with lung disease now essentially what I just told you is we have a immune response that is basically designed to generate an antiviral immune response and that happens from the beginning, but what we think happens in covet 19 disease is that it is actually replaced by a host inflammatory response which, instead of acting like a friend, actually acts more like an enemy in the later stages of disease as it increases the severity of the disease, we know that this disease does not affect everyone equally, probably not surprising because older people are more likely to have comorbidities that make them less resistant to disease in general and, in fact, what What was striking early on was the feeling that the children did not get infected but sadly that is not true and in fact in data that just came out yesterday from the american academy of pediatrics there has recently been a further increase in cases hospitalizations and deaths a percentage increase in children compared to the percentage increase we've been seeing in adults plus there's a single inflammatory syndrome ome that has been recognized in children to be similar to kawasaki disease, which is an inflammatory disease of unclear etiology, but what you can see on this slide is that between 2015 and 2019, before the advent of covet 19 disease, there were sporadic cases of non-severe kawasaki disease and occasional severe cases, but look at what happened in 2020, all of a sudden this huge increase in infections, we think is due to a post-inflammatory disease or post-infectious inflammatory response is still being investigated what exactly causes it, but it is critically important in relation to the development of vaccines for children.
I'd like to say a few words about diagnostics now as a key component to try to narrow down what you're probably most familiar with is RNA testing, which is pcr, and this is what's being done across the broad institute for all college students from mit and harvard. These RNA tests use the polymerase chain reaction to amplify bits of a viral RNA so they don't tell you if what's being amplified is actually infectious or not, they just tell you that there's viral genetic material in there and if you look like it was done in a massive general hospital with RNA detection rates after hospital admission, what you see is, uh, the percentage of admitted people who start out with a positive result decreases over time, but some people remain positive for four weeks or more, the question is what is the See people infectious all that time because right now we are using the RNA detection assay as a yes or no assay.
Well, it turns out that there is a decline in infectivity over time to the point that the CDC revamped their definition of recovery to mean 10 days after symptom. onset and at least three days of the absence of symptoms it's really critical that we develop an assay that we don't have yet that tells us that it measures the infectiousness of a person now another diagnostic test that has been developed is called is a category called antigen tests where you're not looking for biogenetic material, you're looking for viral proteins like the membrane proteins in blue or the spike protein in brown here and the way these diagnostic tests are done is very very similar to the point-of-care diagnostic test which is used as a pregnancy test where what one does is put a detection strip in the urine in the case of a pregnancy test and in the case of an expect and in the case of covid 19, ideally you would use saliva or a swab nasal and then I would use a swab that would tell you if you're infected or not by having a band or two on this uh on this lighted strip these are are now they're actually available they're less sensitive but, in fact less sensitive may actually be better so lets think about the different uh uh assets i just told you about rna based tests are much more expensive and require really much more extensive machinery although that can be addressed as well , rapid antigen tests are much cheaper, the sensitivity is lower, but the scalability is higher, it is easier to reach underserved areas, it is easier to test frequently, it is easier, it is easy to use, but at the same time less now they are not.
Quantitative RNA tests can be quantitative, but we haven't used them that way and I think there's a movement underway to do that and there are issues in the supply chain that are predominantly for the RNA test but not so much for the rapid test. of antigen. So another important diagnosis is to find out who has already had the infection and this is done by testing for antibodies, which are proteins in the blood that are generated in response to the infection. When someone gets infected, there is initially a wave of virus that produces the immune response. it responds by making antibodies, and ideally these antibodies, after the infection is cleared, drop to a level and persist to protect against further infection in the future.
If you look at the antibody responses in people who are hospitalized in the same cohort, you can see that they arise. slowly over time and within about three weeks almost everyone has antibodies um so they're sorry so we have ways to really track the infection, find out who's infected um and these antibody tests are going to be a really important epidemiology. tool let's go ahead and talk about what the treatment prospects are um there are basically two approaches that are generally being taken one of the ones that I went after is antiviral therapies that directly target the virus and an example of this is rem of severe remember at the beginning i told you that diana brainerd was getting calls in south africa to launch a drug that had been developed for ebola that drug ran desperate and now it has been shown to have some effect now the important thing to note in this article that published in the New England Journal is that although remdesseviere does have an effect on speeding up recovery time, there is no change in mortality which is statistically significant so it's really a marginal benefit and it needs to be given intravenously we need drugs that can be given orally can be given early in disease onset or in a disease later firmness and having an effect that probably makes a big difference when the drugs are given in terms of their ability to produce an effect and I'll come back to that, another approach is to use sars kobe 2 neutralizing antibodies and these can come from people who are convalescing. plasma that has been granted an emergency use authorization and has been the subject of much controversy as to whether another therapy on the horizon actually works is monoclonal antibodies that can neutralize the virus that could be given prophylactically or potentially therapeutically, but those are not yet another authoritative way to approach therapy is to have targeted therapies to block the cytokine storm so these are host targeted therapies like interleukin 6 antibodies which is elevated is a cytokine pro-inflammatory and helps create this cytokine storm uh and uh another one is dexamethasone, a steroid, dexamethasone has been shown to have some effect, and it's used now, but there are many trials going on and there's still no clear candidate for a medication that actually meets the requirements.
I think it has an impact of being readily available orally ingestible fast-acting and active during all phases of infection, so let me move on. Now I'll talk a little bit about what are the prospects for vaccines, which is really what I think It will be difficult for us to get out of this pandemic again. A basic concept to make sure we are our basics to make sure we are all on the same page immunity is protection against an infectious disease if you are immune to a disease you can be exposed to it without becoming infected or you can have a very attenuated infection such that you don't even take into account that you have been infected, immunity can be induced by at least two different mechanisms, one is the infection itself and that hopefully leads to immunity for any subsequent encounters by spawning e.g. antibodies that persist, another is by immunization, which is the administration of a vaccine product. which stimulates a person's immune system to produce immunity to a specific disease by protecting that person from the disease, in other words, it is training the immune system to attack the virus without the person having ever seen the virus given just one serving of the virus into a vaccine and using it as your training vehicle so right now there are probably close to 200 vaccines in development in terms of where we are in human trials there are a plethora of vaccines that have already entered human trials 23 vaccines are in phase 1, which is the first phase of the study where they test whether the vaccines are safe and determine what kind of doses can be tolerated phase two there are now 14 vaccines in that phase which is an expanded expansion of the trial phase one to get more safety information and learn something about immunogenicity phase three trials of which there are nine is when large trials of efficacy I think you've all heard that the goal is to determine the efficacy of a vaccine as quickly as possible and the way that's going to be done is to dramatically increase the number of people who get the vaccine so the planned trials are somewhere between n 30 and 50,000 patients because you have to have enough infections to show that the approved vaccine works better than the placebo finally there are three vaccines that have been approved for limited use earlier not by the fda but by other countries china and russia in particular , but there are still no vaccines approved for full use.
There are four different general categories of vaccines that are being sought. One is genetic vaccines. using one or more genes to stimulate an immune response uh inactivated viral vector genes uh sars cov2 is another approach being done in part here in boston by dan baruch in collaboration with jansen and also by astrazeneca in collaboration with oxford this is the use from another virus to deliver v2 genes to cells to stimulate an immune response a more standard approach that has been used for years is the viral protein plus adj uvant this is a bit further down the pipeline but uses the cyrus cov2 protein or the protein fragment along with something to help stimulate the local milieu where the injection is made to stimulate an immune response and ultimately inactivate sars cov2 which is just whole virus inactivation um which has also been used um in the past and is what the chinese have already started to use in some circumstances let me tell you a little bit about what we know from the work that we've done here in boston uh this has been uh dirig gone by dan berut one of the founding members of the reagan institute who is also a medical scientist um and at beth israel deaconess medical center as soon as the virus sequence was published dan ordered synthetic genes to begin vaccine design based on a existing collaboration with jansen johnson johnson in late january to work together then tested the vaccines in animals during february established a challenge stock and by the end of march already had data suggesting this was immunogenic in monkeys and jansen made the decision to go ahead with increasing production in case subsequent studies showed that they were, um, that the vaccine was safe and effective.
The first human studies are to be done this month and it is expected that in early 2021 there will be a massive scale-up and an emergency use authorization for the vaccine, um, hereare the data in monkeys in the sham vaccination red on the left is the composite for 10 animals you can see there is a marked increase in virus in the in this case after vaccination and then challenge but on the right is see the marked difference using the spike protein as the vaccine antigen and of the four animals that were in these two never actually had a virus miss and two of them had a markedly attenuated level of virus in their bloodstream so So the goal here is that instead of what happens with infection where you generate an antibody response, what will happen here is that through vaccination you will generate antibodies and then once the person encounters the virus, it What will happen will be minimal infection or indeed no infection related to a massive rise in antibodies when the true infection of the virus is found, so how are we to know if a vaccine is effective? ?
Well, we have to test it in a place where there is a lot of transmission, and unfortunately in the world there is still a lot of transmission happening most of the time. in asia but also in south africa south america and north america and growing numbers in europe and the new york times on the front page this morning there was an article about the concern in spain that there is an essence of recruitment of new cases um south africa has had a major spike but that's gone down but it's with a general reduction in activities we also know as shown in the New York Times vaccine tracker that we're seeing a lot of cases of infection a uh that's being detected at universities, which can be another place to test a vaccine, although a lot of these actually go more into online education, so as we go forward we'll have to ultimately prioritize and decide what are the vaccines that really do we want to take and what do we really want to promote to make 7 billion doses to be able to make them available to the whole world the only question is will a vaccine protect from the i Infection or from or Does it simply protect from disease? and ideally we would like to have a vaccine that completely protects from infection which would be an antibody based vaccine to get the virus free before it can infect cells but even something that protects from disease and keeps the virus low enough that cells people that people won't pass on would be extremely beneficial and that would probably depend on the T cells how many doses does it take for protection well if you need three doses given over six months to get to protection that means there is a vaccine available for Giving it in December won't protect people until next June.
Will there be enough new infections to show that it protects? I just went over how soon the vaccine will be available and here I think one has to take into account when the first vaccine is in a vial and it can be given to a person versus when that vaccine is available worldwide and you can go to the office from his doctor and he has it on his shelf or shelf and he can take it out and and uh and give it to him and that will require massive scale and I think we all hope that multiple vaccines really hit the finish line because none of these will easily make it to level seven billion doses for the vaccine that dan baruch is doing with the reagan institute and bi dmc the um have committed to doing a billion doses um so the next topic is enough of the vaccine that's being made it's going to be a challenge but people are expanding that right now a critically important and critical question is whether the vaccine works regardless of age most vaccine trials don't include people who s With much older, the few that have in humans have shown that people who are more susceptible in terms of age are less likely to mount an immune response to the vaccine vectors posed to them.
Another critical question is whether a vaccine requires a cold chain and this is really critical when one thinks about global delivery if necessary. keep the vaccine on dry ice and must deliver it in rural areas of Africa; Also, if you have to aliquot the vaccine once it gets to the community where you're trying to administer it, that requires special facilities and special measures that will make it much more difficult, so ideally we don't want any supply chain requirements. cold how long lasting is the immunity that the vaccine induces well there have already been some suggestions of reinfection of people who have already been infected the work of shiv pillai suggests that the antibodies that are produced are are are are somewhat abnormal in the sense of that the lymph nodes themselves are not normal they don't have uh generate germinal centers um so I think I personally think that t It is not yet known whether these immune responses generated by natural immunity actually provide long term protection and the Time will tell that another critical question is whether the vaccine-induced antibodies ameliorate the infection or is it even possible that they will. they can contribute to multifocal inflammatory syndrome in children and the other thing that's not on this slide is that children are actually people under the age of 18. wave of these vaccines as we're looking at safety, but when trials are done in people 18 to 65, the question is whether it will be necessary to do a full set of separate studies in children to get a license to give these things to children and know that they are safe for children, so this is a very important point that I don't think has been given enough attention. at least it's not clear from what i've read what the actual plans are for the development and licensing of these vaccines for children so i think as we wait for a vaccine we have to ask ourselves what else can we in the boston area do um and cambridge i think as a group of scientists we recognized that this was going to be a really challenging problem and we felt we had something to contribute actually we felt we had something to contribute on a larger scale if we could just get everyone to collaborate together so March 3rd I had, uh, I think for all of us it was a really unique experience where we got together with about 85 scientists from harvard mit umass tufts and boston university to talk about what we as a scientific community can do and a clinical community could do to address this pandemic and what resulted was the establishment of the Massachusetts Consortium on Mass Pathogen Preparation PCR, which It has been an extraordinary experience for everyone involved.
I have never seen the kind of collaboration that has evolved from this consortium. We have six different working groups in areas ranging from clinical and outcomes research to diagnostics, therapeutics, pathogenesis and vaccines and epidemiology um uh and a lot of collaboration and sharing that's been going on, we've also been collaborating closely with uh researchers in china who are at the uh guam show institute for respiratory health uh which has been a collaboration fabulous and i am very optimistic uh given the amount of people working on this problem and the selflessness with which people have been working that we will make real progress in the future i think we have already seen extraordinary progress up to this point i think the Another thing we can do is follow the science.
We know how transmission occurs and there has been a lot of talk about it. e the droplets versus the aerosols and how long they stay airborne etc but I think the critical experience The equipment has really been done and the fact is we know how to prevent transmission and that experiment was done in the hospitals where everyone was using masks, you couldn't really achieve distancing, but you could wash your hands and what we didn't see was major outbreaks among healthcare workers, in fact overall the incidence of infection among healthcare workers is less than in the community i think that shows us that masks work and i think as long as we all work as vigorously as we can find solutions in terms of therapies and vaccines if we wear our masks we will prevent transmissions from happening so let me draw some conclusions one is that advances in other fields have clearly accelerated responses to covet 19. everything we What I did at the Reagan Institute it was based on things we learned from working with HIV, including the complete backbone for Dan's vaccine, Sars Kobe 2 infection is transmitted before Sy. mptoms that's how it spreads so quickly and why it's so important that everyone wears masks, the infection results in a hyper-inflammatory state that involves multiple organs and that's what makes what we think contributes to a lot of pathogenesis, currently there are no highly effective treatments even though there are some that have marginal impact, but we really need better medicines and while we wait for a vaccine, effective prevention can be achieved with masks, physical distancing and hand washing, there has been a unprecedented progress toward a vaccine, we have to be sure that the vaccine is safe and effective by the time we deliver it more broadly and clearly, there is still a lot to do and a lot that people, no matter what their discipline is among the students who are listening to this talk, it intersects with a pandemic, either in the scientific field, the psychological field, the um, the tera field. peutic the economic field, etc. so we can all contribute um to a solution um and with that i'll thank you for your attention and i'm happy to answer a few questions bruce thank you very much um the students have a number of questions uh one is asking you um why do you think we are among the most infected nations in the world, well I think actually you can see that in the tracking that I showed in the last month or so, the number of infections has gone down in the US and that's directly related with increased adherence to wearing masks and social distancing other countries implemented those measures right away completed lockdowns like we did, but they came back from lockdowns with continued, uh, really vigorous adherence to the prevention measures that were available to we, you know, and it's not really a surprise that masks are important, in fact, it's important that you wear a mask to protect other people, I don't think anyone on this call wants to have open heart surgery with th their surgeon doctor and and uh and our nurse uh they don't wear masks they don't wear them because they are afraid of getting an infection from the patient they wear them to avoid infecting the patient we know that masks can do that and so I think that's a critical factor here and one of the unknowns for the future as to whether people will actually adhere to that and whether people will understand that there are times when we need to limit our our own liberties huh to protect the general population huh and there are many examples of decisions that we as a society make to do just that and I think this is a situation where we need to do the same and tara is asking how long after recovery after the infection the antibody test results are still positive, so this is a really critical and unanswered question yet, so We only know for as long as the epidemic has been around and there is evidence that in some people antibody levels are declining to become undetectable for a fairly short period of time.
I did refer to concern about at least four cases of supposed reinfection of people who have already been infected, presumably because the antibodies that we have very good evidence that the antibodies can be protective if they're there, but um, but these people are they've re-infected, we don't know their antibody levels to really know how that correlates, but that's a huge concern and obviously that would have a huge impact for the development of herd immunity which is when enough people have immunity that others won't that the virus can't be easily transmitted through a population because it doesn't have enough not enough susceptible hosts now the question asked was if someone gets infected how long do those antibodies last now i think the data that that shiv has generated suggests for which may not last long, but what about immunization?
How long will those antibodies last? bodies last and that's something else we don't know but my feeling is it's probably going to last longer because instead of trying to generate an antibody response in a lymph node in this one that's infected with live virus in this case you're taking a virus fragment delivering it to a lymph node and the lymph nodes learning how to teach the immune response to recognize it without being affected by ongoing virus replication so I think it's probably two very different things but real time tell Lennon to ask if you can comment on v2 source code mutability and the impact of mutations on our plans to vaccinate. i compare a hiv uh virus sequence from boston with one in south africa, they can be 40 different in theabout uh so we have never tried to try to make a vaccine for a pathogen that t diverse in contrast ours cov2 uh has very few mutations it mutates and the consequence of those mutations on immune recognition is still being worked out but then there is a concern and clearly there, the whole population, the global population of sars has already shifted to some extent and I know that dan has already made another vaccine with a second strain of sars just in case what will be critical is if the mutations that they arise, although we hope that they will be much less than with hiv, if they will really result in escape immune and again uh, this is one reason why we need to do a lot of sequencing and a lot of surveillance to get ahead of this um and um and it may be that, like other infections such as influenza, there is a requirement for um to update immunizations on a regular basis another student requests the genetic vaccine or immunizations that use an inactive viral vector ivado what are the concerns of the long term effects of delivery vectors or methods? or with genetic vaccines, you know there's less experience with them, so the clinical trials that are ongoing now both for other diseases, for example, modern have other pathogens that they've developed vaccines for, so they have more data humans of that DNA.
Vaccines have also been used for other pathogens, so data have been generated in terms of inactivated viruses. We have used them for years. the monkey model looked like an inactivated virus that worked but the concern is if the virus could somehow be reactivated and become infectious and I think that tempers the enthusiasm for inactivated vaccines but I think there are ways to make an activated vaccine be safe and um but that's the main concern, another concern is that it's more labor intensive and expensive to make inactivated vaccines because you have to grow a lot of virus to be able to or do that and these fully synthetic approaches that can be used like with mrna are potentially a real advantage if we can do that without having to rely on cell culture and other aspects that are required for more traditional approaches many students had questions about reinfection and the possibility that reinfection is a consequence of the antibodies just not doing what they should do do you have an opinion on reinfection how come the extent to which it happens yes the implications and there is another concern about reinfection based on dengue virus uh and that is if the antibodies could make things worse the second time one of these reinfection cases didn't alarm people it seemed like it was worse the second time but so far there's no evidence from the earlier sars data which I think is convincing there's no evidence there's no evidence to suggest that there is this phenomenon of antibody dependent enhancement I think in terms of protection against infection antibodies are going to have antibodies neutralizing. you will be required to do that upon reinfection so not everyone generates sufficient levels of neutralizing antibodies probably from their first infection although I think T cells may also play a very important role in reinfection cases because if the virus slips through the first defense of antibodies and enters cells, then T cells are the main effector mechanism that can kill the virus and so I think attention to vaccines that do not just produce antibodies but they also produce T cells is important, also there is a second type of T cell besides the killer cell, those are helper cells that help orchestrate an effective antibody response in those germinal centers and therefore generate responses of coveted specific helper cells, I think it may also be very, very important, particularly for the possibility of possible reinfection Bruce, I we really appreciate you giving us an introduction to the disease, the virus, the pandemic thank you very much and see you again next week thank you very much enjoyed it

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