Lecture 1: "COVID-19 and the pandemic"

hello everyone we're about nine months into the covid pandemic in that time a remarkable amount of information has been learned about the novel coronavirus and about host cell biology immunology epidemiology and clinical disease there are complexities in these subjects that confound even the experts the purpose of this course is to learn what we know about these subjects from the world's top scientists i'm richard young and together with fukundo batista and our teaching assistant linda feyen we are core faculty for mit's course 700 on covet 19 sars kobe 2 and the pandemic i'm going to make a few remarks the students who are registered for this course and then introduce our first speaker students if you miss any of the following instructions you can find them in the courses canvas site first live attendance of lectures is encouraged but not required recordings of the lectures will be posted with a link on the canvas site your ta lena will post an after lecture prompt as a survey on canvas a response to which will be required before the start of the next week's lecture answers will be graded for participation and students need to participate in at least 90 percent of these prompts to pass the class lenna will hold a session mondays from 1 to 2 p.m except for holidays reviewing relevant basic material to help you better understand the next day's lecture recommended reading and other reading materials are posted on the canvas site and will be suggested alongside the prompts students are encouraged but not required to engage with these materials finally during each session students can submit questions via the q a function and 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 physician scientist and immunologist the founding director of the reagan institute of mgh mit and harvard howard hughes medical institute professor a professor of medicine at harvard medical school and a professor of the practice of medicine at mit he is also adjunct professor of medicine at the nelson mandela school of medicine at the university of kuala zulu natal in durban south africa where he has catalyzed the creation of two important research institutes dr walker is one of my scientific heroes a person who has played a major role in addressing the aids pandemic and who now is helping us address the covet pandemic just last week he and his collaborators published an important story in nature showing that t cells in some individuals can apparently cure hiv infection together with arlene sharp he is the co-director of the recently established massachusetts consortium on pathogen readiness a collaboration among more than 500 local scientists focused on covet 19 research from harvard mit bu tufts umass and the academic teaching hospitals in boston bruce thank you so much for giving the first lecture in our course well rick uh thanks very much i'm delighted to do this um uh so as as rick indicated i'm a physician scientist i i graduated from medical school in 1980 uh came to mass general intending to become a family physician but then something very odd happened which was the emergence of a new disease none of us knew what it was people that had it were dying left and right we had no treatments and it became clear to me very quickly that if we didn't as physicians on the front lines learn from our patients then we would watch a lot of people die so i then uh took the route of both taking care of patients and uh and doing scientific research and have continued to work on on hiv my entire career and in january of this year to put this in uh the perspective i have on it i was teaching a course to mit and harvard undergraduates in kwazulu-natal south africa called evolution of an epidemic and this is a course that uses hiv as a model to try and understand how an epidemic emerges how clues from patients guide scientific discovery and how policy and advocacy influence the course of an epidemic now as chance would have it one of the things that we did was we were visiting traditional healers and as chance would have it one of the people in the course was an mit student who had just returned from wuhan and another was the director of emerging pathogens for gilead a former trainee of mine who had invited along as one of the speakers the student from wuhan started getting text messages multiple times a day from her family talking about what a desperate situation it was there related to this new um this new pneumonia that was emerging and diana brainard the person from gilead was getting phone calls every day from physicians in china asking her to release a drug that they had developed for ebola called remdessevier so that they could try it to see if it had any effect on this new deadly pathogen um it became clear to me from those conversations that this was 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 human disease with a focus on infectious pathogens of global importance and our strategy is really to use cross-disciplinary disciplinary collaboration coupled with flexible funding to try and make advances and we're fortunate to be embedded in i think one of the best biomedical research ecosystems anywhere so we started working on this uh really right away and what i would like to do now as the first speaker is to give you a bit of an overview of what we know how did this pandemic start how does it cause disease uh the the virus sars cov2 what are the prospects for treatment and what are the prospects for vaccines so getting right into this let's put it in the perspective of what we experienced with hiv so hiv was recognized in 1981 but the the infection started being transmitted in the u.s at least as early as in 1978 or even earlier so in 1981 it was clear that something was going on it 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 know actually who had it now let's compare what happened with this particular pandemic so what happened was that patients started coming to hospitals in wuhan with a pneumonia of unknown cause and looking back at this it was the end of december when this cluster of cases happened and there was a really important observation made by healthcare workers and that was that these people had a common uh experience of having been at the uh at this uh at a hunan market suggesting that this might be a transmissible uh agent um that led to the use of shotgun sequencing to identify the ideologic agent and to the development of a diagnostic test based on pcr that all which took four years for hiv occurred in less than a month so an extraordinary tribute to the advances that have been made in science over the years the sequencing allowed scientists to recognize this as a beta corona virus which is an rna virus that has a a single strand of rna and then an outer envelope with a predominant spike protein that's a major target for the um for the immune response uh the origin of the virus is uh is almost certainly from bats originally it also is very closely related to uh coronavirus has been identified from pangolins but likely the transmission went from bat to pangolin back to bad and then to humans although the epidemiology is still not certain on on that score this is not the first pathogenic human coronavirus that we've seen sars in 2003 caused a total of 8 000 cases with a fatality rate of 11 but thankfully the transmissibility of sars was not that high mers came along in 2011 and still persists there have been 2 500 plus 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. we now have 25 million over 25 million cases as of this morning the estimated fatality rate is somewhere between a half and one percent but varies widely depending upon the age group and the and the geography and it's very transmissible i think the important thing for everybody to recognize from this slide is that we can expect to have additional coronaviruses in our future and the big fear and i think what's 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 does behoove us to to monitor for these emerging pathogens why is it that sars kobe 2 has spread so effectively well it's it's in large part because it uh the transmissibility begins before the onset of symptoms and in fact this is very different than mers and sars which only are at peak transmissibility a number of days after onset of symptoms this makes it very hard to to do uh case tracking and and isolation of infectious individuals uh not surprisingly we have a huge pandemic 25 million global cases uh 850 000 deaths and over 6 million infections in the u.s which is uh the most effective country in the world so how is it that sars kobe 2 causes disease um i i'd like because of the diverse audience to start out with just a basic concept of understanding what's the difference between a virus and a bacterium looking here at uh e coli compared in size to sargeras movie 2 i've exaggerated the size of of the virus here compared to the bacterium but there are significant differences between these two um e coli has four over four thousand genes it like other bacteria is metabolically active and it's capable of independent reproduction sars kobe 2 on the other hand has a total of 10 genes and 14 open reading frames it's metabolically inert and it cannot reproduce independently instead it depends on the ability to infect the human host and to commandeer the the human host to actually make the genes that are are normally making proteins for uh for the cell to use for its own purposes to hijack that and force the cell to make viral proteins so that the virus can replicate and and make new copies of itself um when the uh initial infections were identified to be in the in the lungs that immediately focused clinicians on obtaining specimens and trying to find the ideologic agent which is uh which is what happened through sequencing of long epithelial cells and that also led to a search for the understanding how the virus was actually gaining entry into those cells and that led to the identification of ace2 as the receptor there was a head start on this because this is the same receptor that sars uses the original sars coronavirus that is however not the um those are not the only cells that become infected goblet cells and ciliated cells in the nose are are quite infectible and that actually uh probably facilitates uh transmission lung pneumocytes are infectible that's how we get pneumonia the gut is also infectable resulting in diarrhea in some individuals the virus can also infect endothelial cells in circulation and this leads to as thought to lead to a coagulopathy and clotting that results in a great amount of morbidity cardiac myocytes can also express the receptor for further this coronavirus and myocarditis has been another another disease that's been uh that's been noted and it's even uh appears possible that the central nervous system cells can also be infected such as olfactory neurons this infection doesn't happen without the body taking notice and one of the ways the body fights back is that b cells one arm of the immune response start to make antibodies which are proteins that directly bind to the virus they're generated in response to the virus they learn in lymph nodes how to recognize it effectively and then they they target it and destroy it if however cells get infected then another arm of the immune system kicks in uh so-called killer killer cells or cytotoxic t cells these recognize infected cells because once a cell's infected it alerts the body to the fact that something bad is going on inside that cell by presenting viral peptides at the cell surface in the conjunct in conjunction with an hla class 1 molecule a surface receptor on these cells foreign peptide in the hla molecule in the binding groove alerts these killer cells the fact that something bad is going on they recognize that and deliver a lethal hit to the cell killing it and thereby eliminating infectious virus so okay so we have these immune responses that are being generated to this virus the same way that they are to other viruses why is it that they're not doing a better job well it turns out that b cell antibody production is impaired and this is work that's from ship pillai who will be speaking later in this course where he noted through autopsy studies that in fact unlike a normal immune response it gets generated within a lymph node where these germinal centers result in antibody maturation affinity maturation that allows for recognition what happens in in covid19 disease is that these terminal centers don't form so there's a there's an abnormal uh immune response underway that uh that we're all attempting to understand better let me introduce now a second concept and that is to make sure that we understand the difference between infection and inflammation infection is invasion of the body by disease-causing agents their multiplication in the body and then the reaction of host tissues to that pathogen inflammation on the other hand is the body's process of fighting against things that harm it such as infections by releasing chemicals that are also called cytokines that call the immune system into action and recruit other cells so the the second reason why the immune system doesn't do a better job is because it appears that these killer cells are ineffective at eliminating infected cells but they do produce a lot of cytokines these chemical messengers the same the same way infected cells release uh chemical messengers these then act on other cells and activate them to elicit even further chemical messengers and all of this immune activation leads to bystander problems and leads to this uh this hyperimmune state which has been termed an inflammatory storm or a cytokine storm and here looking at a normal lung on the left you can see that the the alveolar air sacs which is where gas exchange happens between taking a breath in and getting oxygen into the bloodstream you can see that those are very fine membranes that allow for ready passage on the right you see what happens in covid19 disease there's this massive infiltration of inflammatory cells marked thickening of the septae and an impairment of gas exchange uh leading then to the to the clinical problems with uh with um with lung disease now essentially what i've just told you is that we have an immune response that's designed to basically generate an antiviral immune response and that happens early on but what we believe happens in in covet 19 disease is that that is actually replaced by a host inflammatory response that actually rather than acting as friend actually acts more as foe in the later stages of disease as there's increasing disease severity we know that this disease does not affect everybody equally probably not surprisingly because the older people get the more likely they're going to have co-morbidities that make them less resilient to diseases in general and in fact what was striking early on was a sense that 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 been recently a greater increase in cases hospitalizations and deaths a percentage increase in children compared to the percentage increase that we've been seeing in adults on top of that there's a unique inflammatory syndrome that has been recognized in children which is similar to kawasaki disease which is a 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 suddenly this enormous spike in in infections we think that it's due to a post-inflammatory or post-infectious inflammatory response what exactly causes it is still being investigated but is of critical significance related to vaccine development for uh for children i'd like to say a few words about diagnostics now as a as a key component to trying to curtail the the pandemic what you're probably most familiar with are rna tests which is pcr and this is what's being done through the broad institute for all of the mit and harvard undergraduates these rna tests use polymerase chain reaction to amplify fragments of a viral rna so they don't tell you whether what's being amplified is actually infectious or not they just tell you that there's there's viral genetic material there and if you look as was done at mass general hospital at rna detection rates following uh uh uh admission to the hospital what you see is that uh the percent of people that are admitted who start out positive declines over time but some people remain rna positive for four weeks or more the question is are these people infectious all that time because we're right now using the rna detection assay as a yes or no assay well it turns out that there's declining infectiousness over time to the point that the cdc revamped its 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 still don't have that tells us that that measures the infectiousness of a person now another diagnostic test that's been developed has is called it's a category called antigen tests where you're you're not looking for biogenetic material you're looking for viral proteins such as the uh membrane proteins in blue or the spike protein in brown here and the way that these diagnostic tests are being done is is very much like the point of care diagnostic test that's used as a pregnancy test where what one what one does is put a um a detection strip into urine in the case of a pregnancy test and in the case of um hang on and in the case of covid 19 you would ideally use a saliva or a nasal swab and then use a swab that would tell you whether or not you're infected by having one or two bands on this uh on this strip light up these are are are now actually available they're less sensitive but in fact less sensitive may actually be better so let's just think about the different uh uh assets i just told you about the rna-based tests are much more expensive and they require really much much more extensive machinery although that also can is being addressed rapid antigen tests are much cheaper sensitivity is lower but scale up ability is higher easier to get to underserved areas easier for frequent testing easier ease of use of ease of use but at least right now they're not quantitative rna tests can be quantitative but we haven't used them that way and i think there's a move afoot to do that and there are supply chain issues that are predominantly for the rna test but not so much for the rapid antigen tests so another important diagnostic is to figure out who's had the infection already and this is done by testing for antibodies which are proteins in the blood that are generated in response to infection when somebody gets infected initially there's a wave of virus that occurs the immune response responds by generating antibodies and ideally these antibodies then after the infection is cleared come down to a level and persist to protect against subsequent infection in the future if you look at antibody responses in people who are hospitalized the same cohort you can see that they come up slowly over time and within about three weeks almost everybody has antibodies um so they're um sorry so we we we have ways to now really track the infection figure out who's infected um and this is these antibody tests are going to be a really important epidemiologic tool let's go on and talk about what are the prospects for treatment um the there they're basically two approaches that in general are being pursued one is anti-viral therapies that directly attack the virus and uh an example of this is rem de severe remember in the beginning i told you diana brainerd was getting calls in south africa to release a drug that had been developed for ebola that drug was run desevere and it's now been shown to be to have some effect now the important thing to note from this paper that was published in the new england journal is that although remdesseviere does have an effect in in speeding the time to recovery there's no change in mortality that's statistically significant so it's really a marginal benefit and it has to be given intravenously we need drugs that can be given orally that can be given early in the onset of disease and or in later disease and have an effect it probably makes a big difference when drugs are given in terms of their ability to make an effect and i'll come back to that another approach is to use neutralizing sars kobe 2 antibodies and these can come from convalescent plasma which has been given an emergency use authorization and has been a subject of much controversy as to whether it really works another therapy on the horizon is monoclonal antibodies that are able to neutralize the virus that could be given prophylactically or potentially therapeutically but those are not yet licensed another way to approach therapy is to have directed therapies to block the cytokine storm so these are host-directed therapies such as antibodies to interleukin 6 which is elevated it's a pro-inflammatory cytokine and and helps to create this cytokine storm uh and uh another is dexamethasone a steroid uh dexamethasone has been shown to have some effect uh and is now being used but uh there are lots and lots of trials that are underway and still no clear front runner of a drug that's that truly meets the uh the requirements i think to have an impact of being readily available orally ingestible rapidly acting and and active during all phases of infection so let me move on now to talk a little bit about uh what the prospects for vaccines are which is really what i think it's going to take for us to get out of this pandemic again a basic concept to make sure that we're uh our basic concepts to make sure that we're all on the same page immunity is protection from an infectious disease if you're immune to a disease you can be exposed to it without becoming infected or you can have a very attenuated infect infection such that you don't even notice that you've been infected immunity can be induced by at least two different mechanisms one is infection itself and that hopefully leads to immunity to any subsequent encounter by generating for example antibodies that persist another is by immunization which is the giving of a vaccine product that stimulates a person's immune system to produce immunity to a specific disease protecting that person from disease so in other words you're training the immune system to attack the virus without the the person ever having seen the virus by giving just a portion of the virus in a in a vaccine and and using that as your 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 is a plethora of vaccines that have already entered human trials 23 vaccines are in phase 1 which is the first phase of study where you test whether vaccines are safe and you determine what sort of dosage can be tolerated phase two there are now 14 vaccines in that stage which is an expanded uh expansion of the phase one trial to get more safety information and learn something about immunogenicity phase three trials of which there are nine is when large efficacy trials are begun i think you've all heard that the goal is to is to determine efficacy of a vaccine as quickly as possible and the way that that will be done is by dramatically increasing the number of individuals that receive the vaccine so the trials that are planned are somewhere between 30 and 50 000 patients because you you have to have enough infections occurring to show that the vaccine works better than approved than than the placebo finally there are three vaccines that have been approved for earlier limited use not by the fda but by other countries china and russia in particular but there are no vaccines yet approved for full use there are four different general categories of vaccine that are being pursued one is genetic vaccines the moderna vaccine here in boston is one of those that based on messenger rna dna is another form these use one or more genes to stimulate an immune response uh genes from uh sars cov2 inactivated viral vectors is another approach that's in part being done here in boston by dan baruch in collaboration with jansen and also by astrazeneca in collaboration with oxford this is the use of another virus to deliver v2 genes to cells to stimulate an immune response a more standard approach that's been used for years is viral protein plus adjuvant this is a little further behind in the pipeline but it uses cyrus cov2 protein or protein fragment along with something to help stimulate the local milieu where the where the injection is made in order to stimulate an immune response and finally inactivated sars cov2 which is just inactivation of full virus um which has also been used uh in the past and is what the chinese have already started using 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 led by dan berut one of the founding members of the reagan institute who's also a physician scientist um and at the beth israel deaconess medical center as soon as the virus sequence was released dan ordered synthetic genes started vaccine design built on a collaboration already existing with jansen johnson johnson by the end of january to work together then tested the vaccines in animals during february established a challenge stock and by the end of march i already had data suggesting that that this was immunogenic in monkeys and jansen made the decision to go forward with with making scaling up production in case the subsequent studies would show that they were um that the vaccine was safe and effective the first human studies are going to be done in in this month and the expectation is by early 2021 there will be massive scale-up and emergency use authorization for the vaccine um here are the data in monkeys on the left sham vaccination red is the composite for 10 animals you can see that there's a marked increase in in virus in the in in this case following uh following vaccination and then challenge but on the right you see the mark difference using uh the spike protein as a as a vaccine antigen and of the four animals that were in this two of them actually never had a blip in virus and two of them had a markedly attenuated level of virus in the bloodstream so um the 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'll generate antibodies and then once if the person then encounters virus what will happen is either minimal infection or in fact no infection related to a massive increase in antibodies when they encounter that the the true virus infection so how are we going to know if a vaccine is effective well we have to test it in a place where there's a lot there's a lot of transmission and sadly in the world there's still a lot of transmission occurring most of it in asia but also in south africa south america and north america and rising numbers in europe and the new york times on the front page this morning was an article about concern in spain that there's a recruit essence of new cases um south africa has had a major spike but that has dwindled but it's with extensive curtailment of activities also we know as shown in the new york times vaccine tracker that we're seeing lots of cases of infection at uh that are being detected in colleges which may be another place to test a vaccine although many of these are are actually going more to online education so as we move forward we're going to have to ultimately prioritize and decide what are the vaccines that we really want to want to take and and what do we really want to promote to make 7 billion doses to be able to make it available for the entire world the one question is will a vaccine protect from infection or from or does it just protect from disease um and ideally we'd like to have a vaccine that completely protects from infection that would be an antibody based vaccine to get free virus before it can infect cells but even something that protects from disease and keeps virus low enough that people that people won't transmit would be extremely beneficial and that would likely depend on t cells how many doses are needed for protection well if you need three doses given over six months to get to protection that means that a vaccine available to be given in december won't actually protect people until next june will there be enough new infections to show it protects i've just gone over that how soon can the vaccine be available and and here i think one has to be aware of when the first vaccine is in a vial and can be given to a person versus when that vaccine is available worldwide and you can go into your doctor's office and he's got it on his shelf or her shelf and can pull it off and and uh and and give it to you and so that's going to require massive scale up and i think all of us hope that multiple vaccines will actually make it to the finish line because it's none of these is going to easily make it to the level of seven billion doses for the vaccine that dan baruch is is making with the reagan institute and bi dmc the um they have committed to making a billion doses um so the next topic is kind of enough of the vaccine being made it's going to be challenging but people are scaling that up right now a critical and critically important question is does the vaccine work regardless of age most of the vaccine trials are not including people that are much older the few that have in humans have shown that people that are most susceptible in terms of age are less likely to make an immune response to the vaccine vectors that they've been given another critical question is whether a vaccine requires a cold chain and that this is this is really critical when one thinks about global delivery if you have to keep the vaccine on dry ice and you have to deliver it to rural areas in africa moreover if you have to aliquot the vaccine once you get to the community that you're trying to administer it in that requires special facilities and and and special measures that will make it much much more difficult so ideally we want no cold chain requirement how durable is the immunity the vaccine induces well there already have been some suggestions of reinfection of people that have already been infected shiv pillai's work suggests that the antibodies being produced are are are are sort of not normal in that uh the lymph nodes themselves are not normal they don't uh have uh generate germinal centers um so i i i think personally i i think the word is still out um or the uh it's still unclear whether these immune responses that are generated by natural immunity actually do provide long-term protection and time will tell another critical question is do vaccine-induced antibodies enhance infection or is it possible even that they may contribute to multifocal inflammatory syndrome of children and another thing that's not on this slide is that in fact children is uh are people yet less than 18 years old is a whole other category of individuals that appropriately are not being tested right now in the first wave of these vaccines as we're looking for safety but when the when the trials are done in people that are 18 to 65 years old the question is will there need to be a whole separate set of studies done in children uh in order to get licensure to give these things to children and know that they're that they're safe in children so this is a a really important point that i don't think has been uh has been given enough attention at least they're it's not clear um from what i've read what the actual plans are for uh development and licensure of these vaccines for children so i i think while we're waiting for a vaccine we have to ask what else can we do um we in the boston and cambridge area i think as a group of scientists recognized that this was going to be a really challenging problem and we felt we had something to contribute in fact we felt we had something to contribute on a grander scale if we could get everybody collaborating together so on march 3rd i had uh i i think what for all of us was a 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 could do and a clinical community could do to address this pandemic and what came out of that was the establishment of the massachusetts consortium on pathogen readiness mass cpr which has been an extraordinary experience for all of us involved i've never seen the kind of collaboration that that has evolved from from this consortium we have six different working groups in areas ranging from clinical and outcomes research to diagnostics to therapeutics to pathogenesis and and to vaccines and epidemiology um uh and a huge amount of collaboration and sharing that's been happening we've also been closely collaborating with with uh investigators in china who are at the uh guam show institute for respiratory health uh which has been a fabulous collaboration and i'm i'm really optimistic uh given the number of people working on this problem and the selflessness uh with which people have been working that we will make real progress going forward i think we already have seen extraordinary progress up to this point i think the other thing that we can do is follow the science we know how transmission occurs and there's been a lot of talk about droplets versus aerosols and how long they stay in the air etc but i think the critical experiment has really been done and the fact of the matter is we know how to prevent transmission and that experiment was done in the hospitals where masks were worn by everybody distancing couldn't actually be achieved but hand washing could and what we did not see was major outbreaks among health care workers in fact at mass general the incidence of infection among health care workers is less than in the community i think that shows us that that masks work and i think while we're all working as vigorous as we as vigorously as we can to come up with solutions in terms of therapeutics and vaccines if we wear our masks we will prevent transmissions from happening so let me make a few conclusions one is that advances in other fields have clearly accelerated responses to covet 19. everything that we've done at the reagan institute has been based on things that we learned from working on hiv including the entire backbone for uh for dan's vaccine sars kobe 2 infection is transmitted prior to symptoms which is how it spreads so rapidly and why it's so important that everybody wear masks the infection results in a hyperinflammatory state involving multiple organs and that is what makes what we think contributes to a lot of the pathogenesis there are currently no highly effective treatments even though there are some that have marginal impact but we really need better drugs and while we're waiting for a vaccine effective prevention can be achieved with masks physical distancing and hand washing there has been unprecedented progress toward a vaccine we have to be sure that that vaccine is safe and effective by the time we actually administer it more broadly and clearly there's still much to be done and much that people no matter what your discipline is among the students that are listening to this talk it intersects with a pandemic whether it be in the scientific realm the psychological realm the um the therapeutic realm the economic realm etc so we can all contribute to um to a solution um and with that i will uh thank you for your attention and i'm happy to answer some questions bruce thank you so much um the students have a number of questions uh one is asking you um why do you think the us is among the most highly infected nations in the world well um i think that uh you can actually see that in the tracings that i showed in the last month or so the number of infections have come down in the u.s and that is directly correlated with increased adherence to the use of masks and social distancing other countries implemented those measures right away they did complete lockdowns like we did but came back from the lockdowns with uh with continued uh really vigorous adherence to the prevention measures that were available to us you know and it's not really a surprise that um that masks would be important in fact it's important to you wear a mask so that you protect other people um i don't think anybody on this call would want to have uh open heart surgery with their physician surgeon and and uh and our nurse uh not wearing masks they don't wear them because they're afraid of getting some infection from the patient they're wearing them to prevent infecting the patient we know that that masks can do that and so i i think that's a that's a critical um a critical factor here and and one of the unknowns for the future as to whether people will really adhere to that um and whether people will um understand that that there are times when we need to limit our our own freedoms uh in order to protect the population at large uh and there are lots of examples of of decisions that we as a 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 about how long after recovery from infection does the antibody test results remain positive so this is a really critical and unanswered question as yet so the we only know as long as the epidemic has been around and there there is evidence that in some people antibody levels are declining to become undetectable over a fairly short period of time there is concern i alluded to for at least four cases of purported reinfection of people that have already been infected uh presumably because antibodies which we have very good evidence that the antibodies can be protective if they're there but um but these people have gotten reinfected we don't know their antibody levels to really know how that correlated but that's a that's a really big concern and obviously that would have big impact for the development of herd immunity which is when enough people have immunity that others won't that that the virus can't easily transmit through a population because it doesn't have enough there aren't enough susceptible hosts now the question was asked was about somebody becomes infected how long do those antibodies last now i i think the data that that shiv has generated suggest why they may not last long but what about immunization well how long will those antibodies last and that's something else we don't know but my sense is that that's likely to last longer because rather than trying to generate an antibody response in a lymph node in this that's that's infected with live virus in this case you're taking a fragment of virus delivering it to a lymph node and the lymph nodes learning how to you know teaching the immune response to recognize it without being impaired by the ongoing virus replication so i think that those are likely to be two very different things but real time will tell lennon's asking if you can comment on the mutability of source code v2 and the impact of mutations on our plans to vaccinate yeah this is another really good question so sars kobe 2 is nothing like uh hiv which which mutates at an incredible rate in fact if i compare a via an hiv uh virus sequence from boston to one in south africa they may be 40 different different in the in the envelope uh so we've never dealt with trying to make a vaccine to a pathogen that diverse in contrast ours cov2 uh has very few mutations it does mutate and the consequence of those mutations on immune recognition are still being sorted out but there is concern then and clearly there the 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 with a second strain of sars just in case what will be critical is whether the mutations that arise albeit we expect them to be far far less than with hiv whether those will actually result in immune escape and again uh this is a reason why we need to do lots of sequencing and and lots of surveillance to keep ahead of this um and um and it may be that that like other infections like influenza there's a requirement for um for updating vaccines on a regular basis another student's asking for the genetic vaccine or vaccines using an inactivated viral vector is what are the concerns of long-term effects of the vectories or delivery methods so with the genetic vaccines um you know there's less experience with those and so the clinical trials that are ongoing now both for other diseases for example moderna has uh has other pathogens that they've developed vaccines for so they have more human data from those dna vaccines likewise have been used for other pathogens so that data have been generated in terms of inactivated viruses we've used those for years the the you know you can ask with you know why didn't we do that approach with hiv in fact uh in the monkey model it looked like an inactivated virus worked but the concern is just whether the virus could somehow become reactivated and become infectious and i think that's tempered enthusiasm for inactivated vaccines but um but there are i think ways to make an activated vaccine safe and um but but that's the main concern another concern is that it's it's more laborious uh and expensive to make inactivated vaccines because you have to grow up a huge amount of virus in order to do that and these entirely synthetic approaches that can be used like with mrna are are potentially a real plus if we can do that with uh without having to rely on on cell culture and and other aspects that are required for the for the 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 need to do do you you have a view on reinfection how that the extent to which it happens yeah the implications so and there's another concern about about reinfection based on dengue uh virus and that is whether the antibodies could actually make things worse the second time around one of these cases of reinfection not to alarm people did look like it was worse the second time around but so far there's no evidence from from the earlier sars data that i think are compelling um there's no evidence there's no evidence to suggest that there's this phenomenon of antibody dependent enhancement i think in terms of protecting from infection antibodies are going to have neutralizing antibodies are going to be required to do that from re-infection so not everybody generates sufficient levels of neutralizing antibodies probably from their first infection i think though that t-cells may also play a really big role in cases of re-infection because if the virus slips through the first defense of antibodies and gets into cells then t cells are the are the main effector mechanism that can eliminate virus and and so i think attention to vaccines that not only produce antibodies but also produce t cells uh is important moreover there's a second kind of of uh t cell besides the killer cell those are helper cells that that help to orchestrate an effective antibody response in those germinal centers and and so generating uh covet specific t helper cell responses i think may also be really really important particularly for the the prospect of potential reinfection bruce we so appreciate you giving this an introduction to the disease the virus the pandemic thank you very much and we'll see all of you again next week thanks very much i enjoyed it

Channel: MIT Department of Biology

Views: 58,050

Rating: 4.8573642 out of 5

Keywords: MIT, Massachusetts Institute of Technology, Biology, Science, Research, STEM, University, COVID, COVID-19, SARS-CoV-2, virus, pandemic, coronavirus

Id: XbIfFY_fJ_s

Length: 56min 10sec (3370 seconds)

Published: Thu Sep 03 2020