TWiV 789: Does delta mean a change?

this week in virology the podcast about viruses the kind that make you sick [Music] from microbetv this is twiv this week in virology episode 789 recorded on august 3rd 2021 i'm vincent draconiello and you're listening to the podcast all about viruses joining me today from ann arbor michigan kathy spindler hi everybody here it's a pleasant 76 degrees fahrenheit which is 25 degrees celsius blue sky with some nice springfield puffy white clouds it's 24c here but it's so cloudy it was really cool this morning um i thought you know this is august it gets cooler also joining us from madison new jersey brianne barker hi it's great to be here um i have basically the same weather as kathy actually you have clear skies there yeah we have clear skies here wow it's all cloudy here totally clouded i should get a a window cam show people it's all cloudy i see the george washington bridge it's very cool and when i go to the studio i'm not going to see it anymore i'm going to see the back of a billboard out the window yeah that is that is a bad part of it yeah but you know it's life you got to move on also joining us from austin texas rich condit hi everybody um 88 degrees uh mostly cloudy it rained like crazy all day yesterday so it's really wet today we got uh 65 humidity dew point 70 73 so it is stickier than usual however i would say that we are experiencing a fairly moderate uh summer in austin we have a lot of excess rainfall we've only had only had three days officially over 100 degrees looking 10 days out in the forecast i don't see anything over 94 okay so i'm not complaining well i i am kind of a little bit inside but not a whole lot and we don't get a lot of over 90 degree days here for sure and today distinctly felt when i went out this morning it distinctly felt like almost full you know that's that august feeling it starts to feel like full and you're like what happened to the summer i think it's going to be summer again next week i shouldn't complain i'm always inside what do i care right which is fine i don't mind so kathy what's up with the asv vaccine town halls oh well we're having them there are a whole lot of them and uh we have at least six of them planned from when this episode drops from august 5th to august 19th so if you know of people who still have questions about the vaccines point them to asv.org education for the free town halls questions asked will be mostly answered except where the answers are science that we don't know the answers to yet where i guess based on the last one i did if you run out of time yeah there's that all right yeah rich you put a little graphic in here what's up yeah you know uh uh months ago in the pandemic i used to give sort of uh almost a weekly um summary of what was going on in austin i was particularly taken with austin publix health austin public health approach to monitoring this because in particular given the vagaries of testing what they chose to do was to track uh coveted hospitalizations in the metropolitan statistical area which is the five counties surrounding austin including travis county that contains austin and then they have a staging thing where they have different colors if you're over a certain amount of uh hospitalizations uh they you know uh it triggers different uh recommended levels of protection and i haven't talked about this for a long time but they're uh their curve well it's classic i mean you can see it uh all over the u.s but i have to say that recently we're up in the red zone again stage five the most uh [Music] urgent uh stage and the uh the trajectory is going straight up just like the others okay so it's a it's a different demographic in a way okay and i don't know what the death curve looks like though i assume that it's uh different than previously um uh because a lot of the people who are most susceptible have been vaccinated but in terms of virus load in the community this looks every bit like previously what's the percent vaccination in uh in austin do you know uh i don't know about boston in particular and you'd have to look up uh you'd have to look it up because that's that app that kathy picked a few weeks ago you can drill right down just last week yeah last week i don't it's not horrible in austin it's probably about average okay but actually this is one of the things uh that gets me you know when when we were coming out when we were really on the uh downswing from the last peak one of the things that we talked about was you know maybe herd immunity is actually kicking in yeah i don't think so okay this tells this tells me i i think this is mostly behavior okay i think it's a combination of vaccine and and uh not taking appropriate uh precautions we could talk about that but but uh i you know my guess is the behavior those two things vaccination and masking and distancing are are what really drives most of this other factors yeah we're going to talk about some of that but and uh you know [Music] uh apparently [Music] um you know 50 vaccination coverage even 60 or 70 percent immune status in the community if you consider that there's going to be people who i have recovered and stuff i don't know what the actual numbers are but it's not enough yeah yes okay uh and i don't think i i think my my my personal attitude is forget about all those hurt immunity stuff and i've said this before if you're thinking i'm not going to get vaccinated because pre uh uh ultimately uh the virus will go away hurt immunity immunity will take care of it uh you're in for a rude surprise because that's not happening this is going to stick around until we're all uh infected or vaccinated yeah i think in terms of disease we'll talk about this it's important to remember and daniel pointed this out it's a different population now being infected right these are people who pretty much don't want to be vaccinated they may have different daniel said they're probably younger on average and they may have different comorbidities so disease comparisons are very hard here in new york today was announced you're going to need to have proof of vaccination to go to restaurants and gyms first city apparently in the world according to reuters so i said to amy what do i have to do and she gave me this app and i failed because i don't live here so i'm not going anywhere i don't go to a gym here anyway and i don't need to go to any new york restaurants it's fine i can get into my studio that's all i need but i think that's good if people really want to go out they'll uh have to do this it's a little app i forgot what it's called it is uh yeah i have it right here new york state wallet it's and you need an excelsior pass come on you got to give it a fancy name so i'm wondering because we don't have anything like that here that i know of um how do how do you get official information like from your vaccine card or from your medical record to be accepted and validated this connects it connects with the cdc where your vaccine information originally went yeah so i see um the place where i got vaccinated had their own um thing oh yeah and so i my actually there's a copy of my vaccine card in my apple wallet on my phone that's cool and so i wonder if i went to new york whether that would be enough actually they should let out of state people in because right otherwise they're going to shoot themselves in the foot in terms of commerce but it didn't work they kept saying we can't validate you okay i'm okay with that you might check some other apps um okay because i know that i have mine i don't need to do it it's fine i don't go to a gym in anywhere and i don't go to restaurants yet so i actually did go to one in princeton weeks ago the textbook authors got together and we went at a senior hour so nobody was in the restaurant we went at five o'clock and it was just us so we had our celebration of the book which we hadn't had yet so um i thought we do have a paper for you which is really interesting today but before we get to that i wanted to go over this document which the washington post published they say it's a leaked cdc slide deck and i you know somebody released because some of the slides are marked preliminary do not release you know but there's out there i thought we'd go through it and we could chat about it and let me i'm going to share this for you who are listening only we will explain it sufficiently so that you can understand it and for others you can see it so there it is and you can still see us on the side there you go so it's called improving communications around vaccine breakthrough and vaccine effectiveness looks like there's something redacted here right i'm wondering if that's something probably the authors yeah oh okay uh and this was uh uh how did you come by this is this linked in the washington post article yeah it's linked in the article i should say it was sent to me by jeff who is the fundraiser i hired for for micro tv a few weeks ago he's out in l.a and he's very active and i can text him at any hour of the day and he responds but he always sends me stuff now which is not what i'm paying him for but don't get upset at that jeff i appreciate it because i don't see all the things and even one of my picks is also due to him as well uh so the link is in the post and if you follow the link you get a pdf and you can download it and that's what i have here uh and it's got this this official cdc thing here but of course anybody could have made this and the pdf looks like it's a a powerpoint presentation that was presented to some cdc group by somebody it's an internal cdc presentation that was my take on this yeah i think it's just as you'll see later it's all about messaging right what kind of messaging we're going to give yeah how are we going to how are we going to how do we parse and how are we going to present the current status of things so yeah and this first slide is about vaccine breakthroughs may reduce public confidence in vaccines vaccine breakthrough cases are expected um and at the end they say it's important to update communications describing breakthrough as rare or a small percentage of cases so they're telling people how to message this well that's correct right yeah we expect a lot of breakthrough we expect infections in vaccinated people right we don't expect the vaccines to prevent infection i think we've messaged that a lot here on twitter it's the fire extinguisher metaphor yeah the exam says the immune system uh is like a fire extinguisher in your kitchen it doesn't prevent fires but you can put them out okay [Music] they say vaccine breakthrough will occur more frequently in congregate settings and it grew at high risk like immune compromised elderly and so forth and one of the bullet points here the public convinced vaccines no longer work booster doses needed so i guess they want to anti-message that right that's good yeah you don't want the public to think that vaccine's not going to work i think that's one of the outcomes of worrying right there ah absolutely yeah and and they they don't exactly say it in the best way in that previous slide but i think the just a part of what they're saying is that because more people are getting vaccinated then you're going to have you know more cases will be in vaccinated people because there are more vaccinated people yeah so something you brought that up yesterday or maybe friday brienne right yeah i my feeling is that with many of the numbers that are floating around now you should always ask the question what's the denominator yes all right so the next one is called drake greater risk of disease hospitalization and death among unvaccinated versus vaccinated people national estimates and there are three graphs here where we're looking at weekly incidents per hundred thousand we're looking at disease incidence hospitalization and death and they're comparing vaccinated in blue and unvaccinated in green there's a eightfold reduction in disease incidence 25 riddle fold reduction in hospitalization and 20 full five fold in death all right and so you know what i did with these numbers is i went and i took them and made them all one in how many so for disease it's one in five thousand and for hospitalization it's one in a million and for death it's one in two and a half million if needed by arithmetic right and is this in the vaccinated individuals yeah yeah that's great that's right we're looking at it another way uh this is completely consistent with the message that we get that greater than 95 percent of the people in the hospital are unvaccinated yeah okay if there's a 25-fold uh if it's there's a greater than 20-fold reduction in both hospitalizations and death if it were 20 fold that means that 5 are uh vaccinated 95 are unvaccinated so it's greater than 95 of the hospitalizations and deaths are in unvaccinated individuals if that number doesn't resonate with uh people then you just i i don't get it so they also have in some red type here at current incidents 35 000 symptomatic infections per week among 162 million vaccinated americans so that comes out to be one in 4.6 million yeah it's pretty low so on the one hand you know you might see on facebook or something like that oh my god there's 35 000 infections okay but the rate is uh is um really small and in uh unvaccinated people it's going to be 20 times that right easily 25 times that okay all right the next slide is a little it's it's it's marked confidential in big in red preliminary data subject to change and i think probably they shouldn't even well if this is supposed to be internal that's fine it wasn't supposed to be exactly because i think this is not going to end up panning out but what it is it's a graph of percent um vaccinated persons hospitalized and this is from the covid net network with january february march april may so you have uh we have percent hospitalized who were fully vaccinated in uh yellow and percent in-hospital deaths who were fully vaccinated and you know in january it's zero and then it starts to creep up in april it's percent 3.1 percent uh percent in hospital deaths who were fully vaccinated and 4.8 hospitalized who were fully vaccinated and then it jumps up in may but they say it reflects increases in vaccine coverage higher coverage and older adults right and the high risk among older age groups for hospital hospitalization and deaths relative to younger people regardless of vaccination status so i would like to see a condition where in fact 100 of the hospitalizations and deaths were in vaccinated individuals yeah that would be good right yeah because that means everybody was vaccinated yeah yeah yeah i mean i i just feel like this is another place we're talking about there are big differences in how many people are vaccinated and that's what we're seeing here needs to be repeated over and over and over again we don't know what the numbers are here do you have any sense for what they might be is it big numbers or small numbers does anyone know in term big numbers and terms to figure out number of deaths were yeah the percentage of deaths and hospitalization in this uh covid net study we could probably back calculate it but we'd have to find some other yeah okay i'm just curious of how much it is but yes if this is mostly older people it's not surprising because some of them will die right and it's a low percentage i think there's nothing to say that the vaccine isn't working here from these data but uh some people are making a big deal out of this i wouldn't be concerned about it at this point i think rich is right 100 should be vaccinated yep uh then the next slide is about how the cdc monitors vaccine effectiveness ve which is the real world effectiveness as opposed to vaccine efficacy in a clinical trial um they use infection transmission cohort among healthcare personnel and frontline workers that's where they study that non-severe disease is case control among outpatients electronic health record data sets severe disease and hospitalization in hospitalized patients older adults including nursing home residents 65 and up national health care safety network comparison to population coverage estimated through immunization registries outbreaks and nursing homes um what's ehr data sets electronic health records thank you people with uh underlying conditions amino [Music] of protection above variant specific vaccine effectiveness all captured above i want to uh pause here for just a second otherwise i'm going to forget this but we're going to talk about some papers in a short period of time that collect a lot of data about the delta variant and how it behaves and a lot of those the papers come from places other than the us singapore scotland uh and uh canada right okay uh and they all involve mining uh health records okay and it occurs to me i'm not sure of this it occurs to me that that's easier to do in other countries that have universal health care or systems with a widespread electronic data gathering which of course we could never do in the u.s because it would violate our personal freedom okay but it really speaks to the power of one of the subtle powers of universal healthcare and uh and a widespread uh electronic data gathering system it allows you to see easily what the heck's going on yeah i guess the extent of that here is much less even though there are electronic health records that's my assumption that's my assumption somebody you know i think there's you know there are networks but there's not an integrated national network as far as i know somebody else can speak to that i think you're correct all right so next we have vaccine efficacy results early evidence in healthcare providers that vaccination may reduce transmission and attenuate illness this is a study the heroes recover study from december 2020 to april 2021 vaccine efficacy against infection 91 percent among fully vaccinated 81 for partially vaccinated compared to unvaccinated vaccinated cases had either fuller partial 40 lower mean rna viral load 2.3 versus 3.8 copies per mill let me let me just ask let me take a nasopharyngeal swab from two people how can you compare and i mean are they using a housekeeping gene or something how can you compare it and say this person is because it's different amounts different numbers of cells remember in the paper we did last week where they counted the number of cells single cells it varies hugely right yeah so i don't know how they would do that i don't know either but uh we did talk about this study uh either when it was a pre-print or part part way through or something but it was our first hint that there were there was going to be data showing that um having a vaccine might reduce transmission yeah shorter mean duration of detectable rna 2.7 versus 8.9 days so that's that i can buy because that's easy enough to figure out right lower risk of febrile symptoms 25 versus 63 shorter mean duration of symptoms 10 days versus 16 days okay that's all been published new england journal um preliminary preliminary here this next slide is confidential preliminary data subject to change preliminary vaccine ve estimates assessing duration of protection for two doses of mrna vaccines so one of them one of these data sets division uh it's a eight integrated health care systems through june 22nd ve against hospitalization 88 percent no evidence of waning immunity 16 weeks post-second dose then we have a second study i iv3 ve hospitalization 87 no evidence of waning through 20 weeks and then the third is the healthcare personnel ve again symptomatic infection 90 no evidence of waning through 19 weeks that seems all good to me right all good yeah good stuff the next one lower estimates of ve for mrna vaccines among immunocompromised populations this is all published 71 against infection seven to 27 days after the second dose of pfizer among immuno-suppressed people versus 90 overall 80 against infection greater than or equal to 7 days after the second dose among people with ibd on immunosuppressive medication inflammatory bowel disease and then 75 against symptomatic covid seven to 27 days after the second pfizer dose fires are bioentech among immuno-suppressed people versus 94 overall and 59 against covet hospitalization among immuno compromised greater than or equal 14 days after the second dose versus 91 so this is not surprising these are people who cannot make an adequate immune response right not surprising at all but not [Laughter] i was gonna say it's not surprising at all but it also speaks to the fact that it is still very important for these individuals to get vaccinated um because they are getting some level of protection even if it is less than what we see in um non-immunocompromised individuals and you can imagine how much worse disease might be in these individuals right not only that if i'm not mistaken there's no evidence for any uh elevated statistic relative to adverse effects or anything like that there's no there's no downside and i think a lot of a lot of people have this sort of knee-jerk notion that if you're immunocompromised somehow you shouldn't get the vaccine it's going to do it's going to do bad things and that's not the case okay it's going to do good things may not be quite as good as if you were fully competent uh but uh it's uh it's a a lot better than nothing and getting the disease if you're immunocompromised is the worst possible situation good point good points all right lower estimates of mrna vaccine effectiveness among nursing home residents any infection including asymptomatic 65 to 75 in different locations and platforms during december 2020 to may 2021 and these numbers are all in the 70s 60s and 70s nhsn national health something network 6276 years old for pfizer 65 for moderna signature healthcare i guess these are nursing home companies right nhsn and signature healthcare 74 in the 54 to 85 age for mrna and la county 75 percent 43 to 89 years of age i think that's a confidence interval that's the confidence sorry i thought that was the age yes thank you so don't ignore the ages that i just gave you nevertheless these are going to probably primarily be older individuals uh probably other um compromising issues so much the same as the immunocompromised population uh it's not a surprise yeah that the efficacy may be uh lower uh and anything is better than nothing and in particular nursing home residents now remember the vaccine trials had some older people but maybe they weren't in nursing homes right and they were healthier in general so this is the real world right ve is the real world so i think it's not inconsistent with the vaccine trials the next one is called vaccine effectiveness and breakthrough example using the screening method i did not understand this [Music] modeling of some sort or another it is modeling yeah so they're modeling vaccine effectiveness um by comparing vaccine coverage in cases to the population and they have a formula for that and this is a recent nursing home outbreak of the beta variant it's the ve estimate 61 against infection 75 against mild disease and 85 against severe illness i think this partially gets at the point of point that we were making before you know rich mentioned that he wanted a hundred percent of cases in the vaccinated individuals yeah and so here they're showing you the relationship between the percent of the population that is vaccinated and the number of cases in the hospital that would be vaccinated and they're modeling what that would look like if the vaccine had different levels of effectiveness i see okay and so if the vaccine was zero percent effective then none of the uh cases would be then we see that basically nobody would be in good shape um yeah but if you have a lot of people vaccinated um then most of the cases in the hospital will be vaccinated and the exact relationship of how that increases um will vary based on the vaccine that we have yeah so the graph the y-axis is the percent of cases who are vaccinated and the x is the percent of the population vaccinated yeah and so they'd have individual lines for different percent vaccine effectiveness from zero up to a hundred percent yep um then the next one is called vaccine breakthrough in long-term long-term care facility residents where coverage is 80 nationally this is again an modeling estimate um for infection 61 cases vaccinated from mild illness 50 and for severe illness 38 of cases vaccinated yeah and so this is this looks like it's the same model yeah but they've now just put the current um data on there in order to kind of use that to give them an idea of vaccine effectiveness which of these vaccine effectiveness lines yeah uh does our current data seem to fall out and they're using the assumption of 80 coverage which we we're not at right but this is a situation where you had 80 coverage this is what you might expect you might expect um for severe illness 35 in 38 of the cases who are vaccinated based on their modeling and using existing data and it makes the point again that there's going to be a certain amount of disease and hospitalization in vaccinated individuals and that doesn't mean the vaccine's not working no and it's not an excuse not to be vaccinated because it'll be worse if you don't get vaccinated right uh so then this is a slide about communications challenges around ve and differential risk you have these are some bullet points vaccines are more effective against hospitalization death more so than against illness more so again infection it's important to acknowledge lower ve against infection although we've always said it right here on twitter it's not going to prevent infection especially the further you get out from the second dose ve estimates represent an average for group rather than individual risk it's modified by age immune immune status need to clarify messages around individual protection it's important how do we communicate this differential risk to the public comparisons to unvaccinated they're relatively stable personal stories examples from outbreaks that's an interesting point there right because that's always what alan says you got to make personal stories part of your messaging so this immediately makes me think you know the cynical out there might look at this and be reminded of you know leaks of talking points among yes political parties and that kind of stuff okay and i want to emphasize that uh this is this is not that these are effectively conclusions based on science and formulated in a way to help public health individuals communicate what the conclusions are and understand the science behind them okay this is not an attempt to pull a wool over your eyes this is a an attempt to communicate the science yeah all this is based on science for sure okay the next section is called delta variant okay so the first slide they took a figure that actually used in my course it's from the new york times february 28 2020 where they have a graph the y axis is um cfr they call it fatality right here but in the original with cfr and then the x-axis is the r-naught you know the the reproductive index for different viruses they have different viruses on the graph they have you know seasonal flu common cold chicken box measles you know some are really transmissible but not so deadly some are not so transmissible but really deadly in the original cysco v2 they had fatality rate from point one to one percent and the r naught was two to three they call that the source cov2 ancestral strain and then they have a box with delta variant which goes from five to eight it looks like and they they say here uh they put some text delta is more transmissible than mers ebola common cold seasonal flu 1918 spanish flu smallpox it's as transmissible as chickenpox actually varicella zoster virus um so i don't know where these data come from because they don't tell as in in contrast to what we've just heard there i don't know how they get this and i so i've asked jeff shayman to come back next week and tell us how you calculate transmissibility from epidemiological data it's a it's modeling of course um but um they don't in my mind okay this is and we've had this conversation about vocabulary uh to death okay uh i uh it's i think for us it's um uh more comfortable to use the word spread rather than transmission okay because that that in our minds in our non-epidemiological minds at least uh sort of generalizes the phenomenon whereas transmission implies mechanism which we don't know mechanism okay but to me this is somewhere along the line there's epidemiology here that measures kind of the rate of spread under the current conditions yeah of this and it suggests uh you know as i presume the epidemiology backs this up that under the current conditions right now delta is spreading faster than the original sargo v2 why i don't know okay there's we'll get into some some possible reasons but that's that's what i take away from this and i look forward to hearing what jeff has to say the um so i think that's good way to put it um as foucher said you know spread is made up of multiple components right it's the intrinsic properties of the virus it's maybe what we would call transmissibility but then there's human behavior right so i would like to know how they factored in the human behavior and the rate of spread because fouche said you can't just use rate of spread of of a virus in a population to calculate r naught or r whatever it is so and in terms of uh describing what changes there might be in the virus the vocabulary that came out of that discussion was fitness talking about the virus being more fit okay which i think is a nice sort of uh catch-all word uh that has no really specific implications uh for mechanism though uh ron had some his own ideas as to what the mechanism might be having to do with uh immune escape uh and you'll be amused uh may be pleased that there was an expert of some sort or another public health official on the pbs newshour the other night that in talking about the delta variant described its increased fitness yeah wonderful as opposed to transmission and i'm thinking whoa does this person listen to twitter that's good so the the um so i want to clarify this because i think we're using different terms here for sure um but uh i don't know if this this blue box is going to stay where it is in the textbooks right i'm just not sure yet and there's enough uncertainty out there i don't in fact the cdc's messaging is not it's mixed on terms of transmission what they call transmission sometimes they'll say it appears to be or and sometimes it is right and i will my pick relates to this um later but what i do want to point out in terms of virulence it looks about the same as the ancestral strain that's the y-axis according to this so that's kind of from february yeah from february right the other thing that we haven't talked about is that you know the difference between our and are not and you know if we're talking about are not then i may have this wrong but i think the it's saying you know what the situation is when the virus first emerges and there are no population mitigations or whatever correct right and the population is naive right um and so you know if that's what we're stating here for measles and smallpox and ebola and so forth then i'm not sure how we can actually come up with a good number for sars kovi ii because we do have mitigations in play and we don't have a naive population and so forth exactly that's lebron said the same thing you can't do or not when populations got some immunity already yeah that actually sort of makes me think i wonder how we have estimates of the other ones yeah without yeah population as well right i think it's very hard and also um uh so the our naught in itself is difficult because it depends on how many people are in the group you're studying right if they're small households or large because that would affect it right as well um and i think arnaud really shouldn't be viewed as a constant i think you know this kind of a graph is a bit misleading saying it's exactly two to three for this virus i'm not sure that that's the case the other thing i wanted to point out is that another way of measuring transmission or spread is secondary infection rate right the number of people who can be infected by an infected person that's been done a lot and a couple weeks ago the report out of public health england the the secondary infection rate for delta went down which probably reflects what people are doing in some way which tells me that that i think is underscoring it's not an intrinsic property of the virus or not entirely that they're looking at because if it changes it by definition can't be right anyway we hopefully will have a good conversation with jeff about this next week but you know he's going to have the epidemiological viewpoint all right so now we have some data here which are i have some issues with delta infections associated with higher viral load and duration of shedding published evidence and india report of lower cycle threshold values and delta breakthrough cases and healthcare workers 47 people ct value 16 and a half compared to non-delta breakthrough 22 people mean ct19 also larger cluster size with delta breakthrough so the cluster size i think is impossible to compare because it just could be that there were more people in in the one outbreak than the other ct values i don't know how you can compare them between people right because as i said you're not standardizing the nasopharyngeal swab and of course it's rna it's not infectious virus which i can imagine that a variant would have would be different than the amount of rna it makes in the cell compared to infectious virus so i think in to this day nobody has ever measured infectious virus shedding and delta versus ancestral which i think would really clarify it for me anyway anyway or as uh one of the listeners said the particle to pfu that is great great point yeah delta infection second bullet point delta infection associated with longer duration of ct less than or equal to 30. median 18 days versus 13 days that's something that daniel mentioned a couple of weeks ago and the risk of reinfection with delta may be higher compared to alpha but only if prior infection was greater than 180 days earlier and the adjusted odds ratio is 1.46 okay with a confidence interval of 1.03 to 2.05 which i would say it's from none to some to twice as much right i think that i don't know thoughts thoughts on this stuff any any ideas uh i'm wait until you get down to the one uh what's is the next slide the one with the three references in it uh no it's maybe more severe one more anyway so i think these are squishy this is squishy data here um i'd be careful because i think you got to be really careful with with pcr data and i want to bring up again i mentioned this on friday this paper from new england journal that daniel talked about on thursday they were looking at infections and vaccinated versus unvaccinated people with delta and they got they said as high pcr viral loads by pcr in both vaccinated and unvaccinated sorry that was the massachusetts study that cdc is going to cite below and and what they're using for saying to mask but in the in the new england journal it said of those people who are vaccinated that get delta pcr positivity over half of them don't have any antigen so something is going on there i don't know it's not a real infection and so you can't just use pcr levels i think that's my view your mileage may vary i just think pcr is not the right way to look at this okay uh that next slide delta variant vaccine breakthroughs may be as transmissible as unvaccinated ah this is the massachusetts study right barnstable and county massachusetts no difference in mean ct values and vaccinated unvaccinated i think that's not right i just don't think that's right okay well the the difficult part is that if you actually look at those data yeah they show basically a curve for those ct values and they show that the ct values are very similar at early time points and then they diverge dramatically as time goes on and so the sort of that question of what does it mean if your ct value is the same at day one but then is way uh higher yeah which means you have less virus at day two or three um does that mean that the virus you were infected with the same amount where you were you're sort of exposed to the same amount and you've correctly fought it does is that an indication of some amount of residual rna as vincent mentioned um and so that was the thing that really struck me was looking at that curve and seeing how quickly the data diverged and that this no difference was really concentrated at just the early parts of that curve so how brienne i did not look at those data how would describe the divergence um so so basically i'm not sure that i can visit the mmwr you want me to put it up yeah so so if you actually look at the data you can see the the um day following infection and so they have ct on the y-axis and they have days on the x and so in the um vaccinated individuals you kind of see this high these these ct values that then go to higher ct values um they actually i i misspoke they said they put the viral loads so it's inversed and they you see a crash and the amount of virus in those individuals um right away whereas you can see you don't really have the same crash in the um people who were not vaccinated and so if you look at the early time points they are the same and it's very obvious and then suddenly you have you know one line that's sort of going straight across and one line that's going completely down now that you've described that that's not it no i'm trying i'm pulling it up myself this is not the the mmwr for the massachusetts the barnstable doesn't have that i don't know right i don't know which one we were looking at you make a you make an important point is that you know when when during the course of disease or infection are these points being taken right um and is that factored into the calculation yeah i think for all these reasons the ct comparisons are very difficult there's another bullet point on this slide it says breakthrough cases reported to national passive surveillance have lower ct by three cycles for delta compared with alpha i don't know what that means in terms of infectivity if anything that's where i'm just worried that that slide is also confidential preliminary data is subject to change if you want to move on and i have me send it to you later i'm happy to do that sure we can do that all right now next slide delta variant may cause more severe disease than alpha or ancestral strains published evidence there are three um there are three publications cited they're not all published one of them is i think two of them are preprints and as alan would say it's not published anyway there's one from canada higher odds of hospitalization i see you admission and death which the odds ratio they give you so hospitalization 2.2 icu 3.87 death 2.37 singapore higher odds of oxygen requirement icu admission or death uh odds ratio 4.9 and pneumonia odds ratio 1.88 and scotland higher odds of hospitalization 1.85 so did you have any thoughts about that rich uh am i am i correct also that's uh i i'm forgetting here and i don't have the papers right up right now uh some of these had some ct values and stuff in them as well as i recall let's take a look here so the first the met archive is progressive increase in virulence of novel sars cov2 variants in ontario so they actually uh looked they they created a retrospective cohort of people in ontario who tested positive and screened for were screened for variants with dates of tests between february and june they conducted mixed effects logistic regression models with hospitalization i see you admission and death as outcome variables models were adjusted for age sex time comorbidities and pregnancy status so they say that um compared to non-uh variance the adjusted elevation and risk for n501y positive variance 59 for hospitalization 105 for icu admission and 61 for death increases with delta were more pronounced so the others were for any variant with n501y for delta 120 for hospitalization 280 for icu admission 137 for death so they conclude there's been a progressive increase in transmissibility and virulence which i think is lumping two different things together and isn't really fair so i'm i'm not sure i mean this is not published i'd like to see it get through pre-review and then we have a paper from it's a report from scotland uh let's do scotland okay that does a a a similar type of analysis looking at both vaccine effectiveness and um uh outcomes vis-a-vis hospitalization severity of illness they say they show that the delta and it's similar sort of thing um looking at uh medical records uh and what virus was there and outcomes they we show the delta variant of concern in scotland was found mainly in younger more affluent groups that's interesting yep that's changing dynamics uh i think that's a behavior thing including vaccination risk of hospital admission was approximately doubled in those with a delta variant of concern compared to alpha with risk of admission particularly increase with those uh with five or more relevant commit uh comorbidities and then they said uh basically that the vaccines uh remain effective against equivalently effective against the two and then so this is another paper that comes to the conclusion that the delta variant which has uh uh spread faster in that population recently has overtaken the previous variants um results in according to their analysis uh a worse outcome measured in terms of severity of illness hospitalization and then there's the uh singapore story which uh i thought was uh remarkable uh among other things because uh they've been able to do such a thorough job of tracing and sequencing from the get-go and they also talk about having it that it being a relatively homogeneous population that would then tend to uh minimize uh those sorts of population very uh variables and they come to a similar conclusion that the outcomes are uh worse that the odds ratio for hospitalization severe disease are greater with delta than the others my takeaway from all these is that these are three independent studies in very different locations uh where delta has uh taken over and they all come to a similar conclusion that the outcome is at least somewhat uh worse so that uh that gets my attention put it that way at the same time personally i think current we don't know i mean a lot more needs to be done we don't know any reasons um and i think this gets in my personal opinion way over hyped in the media because we also don't know i mean that the problem right now is that cases are on the rise okay and hospitals are becoming overwhelmed again and this gets conflated with the circulation the delta variant and the implication is that the delta variant is driving this and to me even if all this other stuff is true it's not necessarily evidence that delta is a major contributor to the increase in cases we're seeing now that's that's my most important point because i think that the tendency there is to minimize uh inadvertently perhaps the contribution of behaviors such as vaccination and masking and in a way it doesn't matter anyway because the only mitigation recourses we have yeah are masking and distancing on the one hand and vaccination on the other hand doesn't matter if it's alpha or delta or beta or whatever okay there's a limited amount that we can do and there are things that we can do get vaccinated stay away from each other i flashed back to the figure that you showed in the beginning of austin where i wanted to ask you where you know what were the times of the previous two peaks but again it doesn't matter those peaked and they were without there being a delta variant you know they were behavior that's right you know we came indoors we led up on mitigations whatever um and so it's the same kind of thing and yeah and nobody's nobody's saying that the vaccine is not effective against delta okay you get uh small decreases in efficacy i don't know in some studies i don't know if they're significant or not so the what needs to be done doesn't change no get vaccinated right uh and in this in a situation where the sort of uh in your community the virus load is going up uh uh short of vaccination which is what really needs to be done we don't need to be in this situation okay um mask up practice distancing in fact so the scottish paper the scottish paper uh which they these findings provide a strong impetus for rapid implementation of vaccination programs yeah any time and i thought the singapore paper was also quite well written they they real they did not go overboard they were very measured uh in their conclusions and their analysis and they you know basically come to the same time but the other thing is in the scottish study as you said these infections are in younger more affluent groups it's a different population so i think it's hard to compare the disease in different populations you really need to be careful with that so as you said it is not a conclusion yet now rich you said no one is saying that delta gets through vaccines but i think in this slide cdc thinks it is because of the pcr loads are the same but i think this is wrong this barnstable county i think it's wrong so so i found the data okay um so it is actually from a med archive pre-print another singapore study um called virological and serological kinetics of sars kov2 delta vaccine variant breakthrough infections multicenter cohort study uh sure stop sharing here i believe you can see yeah um so this is the plot that i was talking about where they look at the unvaccinated and vaccinated individuals unvaccinated in red vaccinated in green and the ct values at different days of illness and they make they actually have a statement that says um ct levels are the same at early days following infection but then they go on to talk about how they are not the same uh later on mm-hmm vaccinated they go way down yeah right exactly and so this was um put on med archive at the same time as those cdc data and i think that this was something that people have been thinking might have been uh related to um sort of behind that bullet point that was unsighted and look at the scatter yeah yes exactly oh yeah uh but this is uh brienne this is great this is uh this is really cool and i was thinking about this this morning i don't know why uh if anyone okay wants to see it okay i don't know why i was thinking about it in this way but it's like that's it it fits the fire extinguisher analogy okay uh in both cases you start off with a blaze and in the vaccinated people you put it out faster right that's exactly how i looked at that um and it said to me okay so you know i i think that this is telling me that the vaccine works um and so that's i i was sort of annoyed when i saw the cdc document that said vaccine or the ct levels are the same because i had seen these same data at the same time and said yeah they're the same sometimes and at other time points they're really not so and it speaks to vincent's point about how it's difficult just to look at raw ct value data exactly uh you at least have to know when during the illness uh the sample was taken okay that it's uh the kinetics are uh uh certainly as important as anything else that's brienne that's great what a great find i like that all right so let's wrap this up here uh the next slide phrase are two dose vaccine effectiveness for alpha versus delta um so they're looking at in confirmed infection symptomatic disease hospitalization or death and from my perspective the two are pretty much the same for hospitalization and death 90 high 90s vaccine effectiveness that's all that matters to me i don't care if there's a divergence in confirmed infection or symptomatic disease in israel a big difference between alpha and delta but in disease it's similar and that's all that matters canada though um similar numbers for symptomatic in both vaccines groups so there's all kinds of scatter here too right yeah the differences that you see for israel don't play out in canada or england scotland no um then this slice has given increased transmissibility lower vaccine effectiveness and current vaccine coverage npis needed to reduce transmission well that's the problem given increased transmissibility if you're assuming that then that then they have some models here uh for um masking you know models what would i happen a two different r naughts two and a half and five no maskings masks unvaccinated only all masking and you can see different outcomes these are models right and it's just masking it's nothing else they're assuming a vaccine effectiveness of 75 to 80 percent for just infection but i don't think infection matters right um all right so what is the difference between these two slides it's the same isn't it i think it is i think it's oh it's an overlapping essentially an animation yeah given higher transmission current vaccine coverage universal masking is essential to reduce transmission yeah well we shouldn't have stopped masking right they don't even have to say to reduce transmission of the delta variant they should just say to reduce transmission i agree i think the focus on delta is crazy the press is saying delta drives everything yeah yes a scapegoat and i think i think it um i think it actually compromises the message because you're gonna have people going to have people saying oh well you know there's nothing i can do about it yeah because it's the virus that's doing this you know probably probably the vaccine doesn't work as well the masking doesn't work as well you know i might as well just go out to the bar and drown my sorrows not true all right summary slides i really have a problem with summary delta is different from previous strains okay it's not a strain it's a variant cdc highly can even the press has got that it's highly contagious likely more severe breakthrough infections may be as transmissible as unvaccinated cases i would object to all three of those but this is an internal document fine bullet point two vaccines prevent over ninety percent of severe disease but may be less effective at preventing infection or transmission i don't care about infection transmission i'm not i don't buy it therefore more breakthrough in community spread despite vaccination i don't agree with that npis are essential to prevent spread okay i think you're going to have a problem getting people to go back to npis frankly since you told them to stop and so many people don't want to do it to begin with i think you have an issue we just had some changes around here and the number of messages i have received from friends who are up in arms and who are upset about that has really surprised me we had the announcement that um faculty students and staff will all have to be vaccinated which contradicts what i had heard earlier could even possibly be the case because i had heard that the legislature said you do that no funding but they somehow figured out oh my gosh finally next steps communication acknowledge the war has changed i disagree the war has always been vaccination improve public's understanding of breakthrough yeah don't call them breakthrough they're infections that happen when you're vaccinated improved communications around individual risk among vaccinated risk of severe disease is reduced tenfold or greater and vaccinated risk of infection reduced threefold i don't think you should message risk and infection reduce threefold i should you should say human vaccines do not in general prevent infection and saris cov2 is no different that's what i would do but i'm not in charge of anything consider vaccine mandates for health care workers okay i think that's a good idea but a lot of people are objecting universal masking okay that's it acknowledgements i think one of the comments that i read somewhere was that uh cdc did not adopt in terms of messaging or whatever all the recommendations from that presentation that was the author's recommendation i see and what actually was done was you know deviated from that at least a little bit so i wouldn't uh on a leaked document i wouldn't necessarily take home that those messages at the end are what the cdc is saying i would say that was what the presenters in that particular presentation thought ought to be said what to see you know go to the cdc to find out what they're saying and also you know with uh with respect to this uh hindsight is 2020 we never should have unmasked you know i'm willing to give them a break on that if you look at that that same curve that i showed at the top of the show about what was happening in austin the cases were plummeting and even you know we were talking even with daniel about how you know maybe uh maybe this is uh hurt immunity actually kicking in yeah sure and part of the cdc's rationalization okay even stated as i recall uh in their um guidelines modified guidelines at the time was that maybe if we tell the vaccinated people that they can take off their masks they never said the unvaccinated people could do it they said maybe if we said that say that the vaccinated people can take off their mass it'll provide an incentive to get vaccinated yeah right okay uh that was a gamble it didn't work okay uh and you know the cdc said every the unvaccinated people need to uh keep masking maybe if they had that it would have worked okay maybe that would have been okay and maybe it should be uh an incentive you know they they uh they did the best they could at the time turned out to be the wrong thing because they said vaccinated people can take off their masses so everybody took off their mass and you know i go around the store we were uh in uh trader joe's the other day and the masking was at about 50 and my wife and i are looking at each other and figuring you know i'll bet you all the people wearing masks are the ones that are vaccinated i think i think they did not estimate human nature very well exactly yeah and exactly it seems to me that i could have told you that you know people who aren't going to get vaccinated are going to not wear masks as soon as they have the opportunity to not wear masks yeah i agreed and i didn't i thought it was a bad idea but nobody i'm not in charge that's because you're so cynical you knew that the unvaccinated people would uh take off their masks i did i do think that they should have factored it they trusted people and that you can't do that especially this country is so divided right yeah maybe 40 years ago but not not today that's actually the most disappointing thing and frankly uh really literally politics aside okay what's disappointing is that over something like this that obviously doesn't care what color you are what your religion is what your politics are it's going to kill you regardless over something like this we can't come together and do the right thing wearing a mask is not difficult it's just not difficult getting vaccinated there's no downside it's easy why all the fuss okay you know when when the japanese bombed pearl harbor people came together okay uh in a in a way this is you know if you want to use the war analogy it's the same thing come together fight a common enemy yeah but we were divided people some people were told you don't have to do it what cdc is telling you can do your own thing you don't have to get vaccinated that's a real problem all right i wanted to do this paper because you know the narrative on stars cov2 vaccines and recovered people you take their serum and you test for neutralizing antibodies you do some kind of infectivity assay where you add the antibodies and you see the antibodies blocking infection and this is in in some ways been a measure of how good our immunity is but i just this paper shows that even an antibody that does not neutralize virus in cell culture in the laboratory can still protect against disease by a different mechanism and i would argue that it could apply to soros covey too we just don't know and you know so people freak out waning immunity waning antibody levels even they don't even bother with the t cells waning antibodies maybe it doesn't matter and so this is the mechanistic basis of protection by non-neutralizing anti-alpha virus antibodies from james earnest autumn holmes catherine bassor mattius mack david fremont and michael s diamond from washington university in st louis and university hospital in regensburg germany by the way uh i was at hamilton montana some meeting a couple of years ago and david fremont was there he came up and he goes i just love what you're doing with twiv it's great thank you david um so this is a model system right they have used an alpha virus infection of mice and the alpha virus these are rna viruses plus-stranded rna viruses um [Music] there's a lot of them there are two classes the ones that cause encephalitis and then the ones that cause arthritis joint pain and so forth so forth encephalitic versus arthritogenic so the encephalitic ones you may have heard of eastern western venezuelan equine encephalitis viruses right there neurotropic the arthritogenic include chikungunya virus one of the favorite names ross river oh nyongyang and mayaro and my arrow virus is the subject of this paper circulates in the caribbean islands south america febrile unless you get joint pain you can get pain the rest of your life chronic arthritis very much like chikungunya can do and no no no way to prevent infection no way to treat it so vincent didn't mention that these are enveloped viruses as well so they're positive sense rna viruses like coronaviruses and they're enveloped around us may i have the envelope and you know uh in cartoon style at least even actually more than cartoon style uh and in terms of lifestyle they they they bear a resemblance to coronaviruses i mean uh you know if you if you show a cartoon of it you got this big spiky thing sticking off the surface that's got the receptor binding domain is it a class one fusion protein vincent it is a class one yeah okay so mechanistically similar at least in terms of getting in um the um there's a by the way i really like their introduction to this paper it's really lays all that stuff out very nicely there's a precursor to this paper i forgot the journal a couple of years ago where they isolate monoclonals against my arrow virus they have a mouse model of infection these they have a bunch that neutralize infectivity in cell culture none of them protected mice against infection none of them when you give the antibodies to the mice and then you infect them so that stimulated this paper and i was wondering this is the mechanistic paper so that's why we're we're doing we're doing this one so here they isolate monoclonal antibodies that bind to the the glycoprotein of my arrow virus they identify them by binding by elisa then they do [Music] neutralization assays they picked 13 on the basis of cross reactivity with other um with different isolates of my ro virus basically they do neutralization assays none of the none of the 13 that they picked had inhibitory activity in cells even at 50 micrograms per mil can you imagine they're disappointed maybe they were happy actually didn't neutralize and they bound virus particles these antibodies bind the virus particle in fact there's a section where they actually map the epitopes of the for the for the antibodies on the virus particle they do an amazing amount of work where they actually do alanine scanning to map the epitopes for the monoclonals to bind and they can say okay there are six different sites where they bind and this is exactly where they bind okay so in terms of in terms of actually doing the science it would be fun to talk to the authors about this because i'm an idiot and if i got this far in the thing i would say okay those antibodies are useful uh but they did the smart thing chance favors their prepared mind right though i don't know if it was chance maybe they were looking for something like this well i think for their previous results where none of the none of the antibodies were protective right they they made them and they weren't protective so they said let's figure out what's going on so they have a mouse challenge model they take uh four week old mice and doesn't the virus doesn't cause disease in in immunocompetent mice so they have to give them an antibody against the type one interferon receptor transiently immunosuppresses them and then you give them subcutaneous virus and they die so now you can ask can you protect that the mice with ant with these monoclonal antibodies so they do they in fact the monoclonals protect but they're not all the same some of them have 100 protection some of them 50 or so and some of them some of them less so and the protection seems to correlate with the binding affinity of the antibody for the particle which they measured previously i didn't tell you that because you would forget it in a moment and it wouldn't mean anything but the met the the better protectors are high affinity and they map to one of two epitopes um one group at the top of the spike of the trimer spike trimer and another uh in in the linker region on the side so there's a difference in protection but they do protect these did not neutralize in cell culture so that's i want people to understand that neutralization is not the only way that an antibody can protect and this is likely not just for alpha virus it's not just for my aerovirus it's probably for many viruses as well this happens to be a great system where they can use it to to point it out so they have the next set of experiments how does this work what's going on how do these protect against disease so they say it must be the fc portion of the antibody the part away from the antigen combining site yeah kathy's model in the background yeah he's got kathy's got her where is it there it is yeah hanging up there we got the two the y right the two tops of the uh oh antigen yeah and the bottom is the fc which combined receptors and so um if you're using igg monoclonals they will bind a fc gamma receptor and they have mice that have been knocked out and don't make those so you infect them you ask can the monocles protect no protection now without an fc receptor no protection isn't that beautiful a lovely experiment in fact the whole paper is lovely i'm thinking about the fc portion for people who you know i don't think about this all the time i'm thinking about the binding portion is you know it climbs on climbs on to the antigen and the fc portion is kind of now what okay yeah what are we going to do with this now and uh that directs the fate of that complex is that fair uh brilliant there it is it is it is and i think that the other thing that this you know tells me is that this tells us that there's a cell involved too a cell with an fc receptor is doing something of course yes is that is that antigen velcro bound in there or something yeah it's a snap i have the same one with different colors and the detachable antigen so that my face on either arm is great cathy important part is the fc receptor which in this depiction is the top the top yeah they got the eyes oriented so that the fc is on top maybe they worked on fc receptors they want to give it prominence right i mean fc's yeah all right so the so the fc receptors are important for protection and so then they do some engineering of these uh monoclonals they they swap them around and it's a reagent that we're going to use later the one that i really like is they introduce an amino acid change in the fc region that prevents a glycosylation that you need for binding to fc receptors and they show that that antibody doesn't protect anymore one amino acid change and that's going to be uh used later they also do some swapping i don't want to talk about those it's a bit confusing the the the glycan change is really good control all right so um they have another model now they say we wanted to try a more physiologically relevant model because we had to immunosuppress the mice right um so it turns out if you give subq virus in the foot of of immunocompetent mice you get joint swelling you get musculoskeletal disease that you can measure you can do sections and look at the the pathology or you can measure viral rna lateral levels um so they can then put virus in with with or without monoclonal and say do we get disease um [Music] and do we get dissemination of the virus so that's a good model i mean the mice don't die you have to work harder to to find evidence of virus reproduction but it's it's a physiologically relevant model because the mice are immunocompetent yeah and that's good because you know in that previous experiment we realized there was a cell involved in this process it's not just the antibody and those cells could have been altered by the lack of interferon right okay so the experiment is they inoculate the virus into the foot and they measure rna so they have to remove the foot where they sacrifice the mice of course and remove the foot the muscle the ankle etc measure rna by pco thousand fold reduction in rna in the ipsilateral ankles with two monoclonals that's the same where they put the virus in right ipsilateral they also see dissemination of virus to the ipsilateral calf muscle the leg and the spleen but not when you treat them with antibodies you don't see any of that dissemination given monoclonals there's no dissemination only one animal had virus in the spleen so that's pretty cool and by the way that monoclonal with the one amino acid change that prevents glycosylation and prevents fc binding doesn't protect from infection i think that's a really nice control so they don't have to use the knockout mice the fc gamma receptor knockout mice for this they also measure ankle swelling as a kind of pathology and they show that ankle swelling is reduced by um these monoclonal antibodies so the monoclonals prevent dissemination and disease really nice and they don't even neutralize infection so they bind fc receptors which fc receptors brianne is thinking on what cell types absolutely i'm guessing it's an fc gamma receptor since it's an igg but after that i'm i'm ready to go yes and of course the knockout mice were the gamma common chain that they knocked out so so the cell type they deplete so monocytes are nk cells they have fc gamma receptors right so you can deplete those from mice with antibodies against the cell type markers on the cell type so they can deplete then they can infect and then they can give antibody so um if you deplete um monocytes the the protection afforded by the antibodies decreases you know these two are 100 now it goes to 40 and 30 percent but if you deplete nk cells no difference nk cells as opposed to yesterday on immune where nk cells made nets here they don't do this yesterday was neutrophils sorry neutrophils yes i get the ends mixed up all the time natural killer so nk self fc receptors do not bind uh and it's the monocytes and um i guess uh cindy would be happy she likes monocytes i i i very much like monocytes um if i had you know thought more i would have worn my monocyte necklace just to talk about this paper um so how do monocytes do this so they do a bunch of experiments i think the coolest one is where they deplete virus from cell supernatants using uh antibody and uh and cells they incubate antibody virus and monocytes together and they centrifuge out the cells and they show a reduction of virus in the supernatant so the viruses are binding to the monocytes by the antibody the antibody binds the virus the antibody binds the fc receptor and they stick to the monocytes and um i guess the idea is that eventually the the virus particles are taken up into the monocyte destroyed they do yeah so basically the idea is that this should activate the monocyte to be phagocytic um when the fc receptor is engaged so back up a minute uh i'm not sure we got the or i understand or that we got the nk cell depletion the nk cell depletion did not affect protection against infection afforded by the monoclonals no change of protective activity there are two big cell types that have the fc gamma receptor monocytes and nk cells right and so they checked both of them to see what would happen if they got rid of those cells and if they got rid of nk cells nothing happened so the mice uh still were protected which told them that nk cells were not the thing that was affording protection right when they got rid of monocytes the protection went away and so that told them that the monocytes were the thing affording okay it's one of these double negative things yeah it's really hard to think about okay so the virus particles with the antibody attached to monocytes they did some assays to show that it's internalized the virus is internalized as brienne said the binding of the antibody tfc receptor activates the monocytes they become phagocytic they internalize the virus and that's the end of that virus once it's in uh monocytes um it's going to be destroyed so that's the mechanism of the ability of these antibodies to prevent infection it's not neutralizing it's not and you know neutralizing can be blocking virus attachment by the antibody it can do other things as well but none of that is involved here here it doesn't even involve the it involves binding the virus particle and then getting taken into a macrophage i think that's really cool so remember that as we look at variants showing up and we look at vaccines yes uh their behavior a lot of the assays that are done with sargo v2 are in vitro neutralization assays okay what's this the metaphor is looking under the street lamp right you look where the light is you can do you can do those assays but those same things don't take into account immunity uh uh cellular immunity yeah neither do they take in the account the potential for this kind of thing okay where it's not neutralizing it's antibodies that do other things okay and really important yes i agree because people get freaked out when they see neutralization activity declining but [Music] well first of all only part of the story not only yeah part of this not only that but um the epitopes uh that are going to do this are different than the epitopes that are going to confer neutralization all right so that's right um they are different you could change the neutralization without changing any of this at all as a matter of fact i think they make the comment somewhere in here that uh some of these are conserved epitopes is that correct or am i talking about is there conservation of the antibodies well conserved in uh different isolates of my ara i think yeah yeah that's correct they do say that but yes so i don't know brandy are you aware of anyone who has looked at similar mechanisms for um sars cov2 antibodies um there's all been a little bit of work but these experiments take a lot more time than the neutralization and so you'd need a bsl3 because you'd need that for saras kobe 2 which yeah so i have not really seen kind of something that's extensive and really shows all of this mechanism so i think it's very important that this be done and we understand the contribution because the reduction in neutralization by these changes may not be as significant as we think it is right i i i think the t cells uh are clearly helping an awful lot but i wonder how much the antibodies the neutralization the classic neutralization how much they they as yes rich said we're looking under the street lamp because we have an assay that is easy to do but yeah i think that one thing that i've realized needs to be communicated to people more and more often is that immune responses are more than one thing i think this is this is a nuance and part of the problem is that the writers who write about this for the mass consumption don't understand that nuance they just want a clear straight story okay the variant is evading antibody that's it we're going to write that and that's that's the whole story but it's very nuanced so this is a beautiful system to make these kinds of observations i think it's a great model system you have you know the ability to make antibodies to the virus and examine them in culture you got a mouse model so i thought really good to introduce this concept that the protective ability of an antibody against disease may not involve neutralization and i think if i remember correctly one of the the there's a cocktail of monoclonals used that were used to treat ebola virus infection i think one of those three made by regeneron is not actually neutralizing and they threw it in there and it works better is that right yeah they make the point uh over and over again in the discussion and this is they're not really knocking their own work they're talking about uh uh partly talking about limitations they're probably talking about where this needs to go uh this is a an animal model uh they need to look for uh what sort of antibodies are made in humans that are relevant in this fashion those are much more difficult experiments to do but you know you think about this in terms of vaccine development right for cyroscop2 they made their vaccine they tested for neutralizing antibodies they also tested for t cells but they didn't do any functional they just said yeah there are t cells that are virus specific but they did neutralization assays and they based everything on that and there's probably more i don't know why they didn't it was a matter of expediency they decided that neutralization was the the the property they were going after uh i think they got lucky i was you took the words out of my mouth i hate to say lucky because there's so much skill involved okay uh but it could have it could have turned out otherwise well i think they had some previous information about the importance of neutralization with some of the other coronaviruses and so they said let's let's assume that those same things are the case i don't know how much they looked into these other functions with those other coronaviruses um in uh making that argument um but they said neutralization seems to work pretty well for these other coronaviruses let's go for neutralization so neutralization works well meaning there's a correlative protection of neutralization versus what disease in an animal model or something is that i believe so yeah i think the developers also had their eyes on the uh cellular response from the get-go there wasn't as much data uh on on on that because the experiments are harder to do yeah but there was always a component of the analysis that says you know let's be mindful of the cellular response because we know that's important interesting word you used there what mine which word yes this paper um as well as a paper we talked about on immune yesterday which was also about a non-neutralizing antibody function for those of you who were not there um have both made me more mindful of how i am putting together my functions of antibodies lecture for my fall immunology class i feel like i maybe undersell things i mention things other than neutralization but i'm not sure i focus on them a lot and now i'm i'm realizing from both of these papers that i want to change how i talk about them yeah i'm gonna i've always had a figure that has different ways to neutralize besides blocking attachment because that's what we're thinking but i want to now yes have another one with other non-neutralizing mechanisms of protection i think that's a good idea yep two comments to make about this paper uh one is about the second author because she's a graduate of the university of michigan uh autumn holmes i met her several years ago first at the maryland asv meeting and then at the minnesota meeting we uh ran into each other again kind of intentionally and so i missed seeing her these last two years but she trained in bert semler's lab so she worked on picornaviruses and seeing the kinds of things that were done in this paper it's like wow she's got a whole new skill set depending on what she did i didn't have time to connect with her and find out um what exactly was her expertise in this and then the second thing uh it's just just a comment and it comes up in a lot of papers um and this is paywalled so it won't work for most of you but figure 3 is a set of graphs of survival of animals and they present the graph and then they present the legend for each of the different color curves in the same order that the software program spits them out in this case it's most likely prism and it's most likely the order in which the data were entered because in fact their antibodies listed in numerical order and it could be so much clearer for someone to look at the figure particularly in us in a oral live presentation but but also in reading paper if you would take each of those legend pieces and rearrange them so that they are closest to the curve of interest so for instance the red and the blue curves are on the top if you moved may 10 and may 108 to the top those are the most protective and it's very easy to see that and match that up with the data in the paper so this is a trick that i learned from jean-luc de mont and i try and teach it to people whenever i can and yeah it's a good idea just makes it much easier to grasp in a hurry yeah this paper's actually open access oh it's nice oh that's right i just now saw that yes so you can check it out all right let's do some pics brianne what do you have for us so as i sort of mentioned a second ago i'm really into thinking about my courses for the fall um and in planning uh for courses and i was going through my course website um and came across this link that i use in some of the classes to some games from the nobel prize website so nobel prize has a set of educational games that are related to different uh nobel prize achievement winning achievements nice um so i use the blood typing game when i describe how agglutination works um in talking about blood typing and so i i've used that every year i was coming across that but they have actually quite a few um fun little games here where you can learn about conditioned learning or chirality or x-rays to the cell cycle things like that so these are a lot of fun i find that the blood typing one makes the point that i want to make in class really well for my students um so i think these are our neat little games that's great that is just great good for the nobel site nice that's really cool rich joe kathy what do you have for us i picked something that's a youtube video put out by the u of m and it's a really cool story about uh now i forget what exotic island place these are these snails are but um the native snails are mostly all extinct except for one species and they were trying to figure out um why that was and in fact a hypothesis was presented maybe almost a century ago but they were able to finally follow up on that and hypothesis was that the snails that were surviving um liked to be uh or spent more time in the sun and so what they did was make these tiny little photo sensors in conjunction with the uh engineering school here and put them both on leaves and on the snails and show that indeed the ones that survived uh spent more time in the sun it's just kind of an amazing uh coming together of biology and engineering that's great hypothesis testing makes perfect sense to me i home to the sun [Music] yeah after spending so many years in buffalo i guess you would right yeah which is great i think it's tahiti oh yes thank you yeah rich what do you have for us i have a book called uh in shock my recovery from death to recovery and the redemptive power of hope by a woman named rana otish i believe that this was a new york times bestseller from a while ago that i read recently because it came up in the context of this annual [Music] conference in honor of my sister-in-law at uh beth israel hospital and basically this is the uh this is an autobiographical account written by a uh uh physician ron odish and in my pick i linked to her the the description of her on wikipedia um where uh uh early fairly early in her career though she wasn't attending at the time i believe she was pregnant and had a near-death ex hemorrhagic experience that was misdiagnosed because it resembled a late pregnancy bleeding disorder um and that misdiagnosis actually led to a longer struggle over a period of uh years really to finally figure out what the problem was and and and address it it was some benign uh tumors in her liver um but she had a god-awful experience and was near death more than once and importantly this is one of these classic uh dr s patient stories okay where now she experiences medicine from the perspective of a patient and comes to realize uh where a lack of compassion can have such a profound negative impact on the patient's experience and you know maybe even their well-being and she talks about how the medical profession in trying to that traditionally in trying to cultivate a certain amount of resilience and toughness in physicians basically trained people to [Music] suppress their otherwise compassionate instincts and that that's counterproductive and this turned her into an advocate for uh compassion and uh in medicine and it's a it's a great story did you mention this friday to uh i was just gonna ask that same question karen i think you someone mentioned a book was it you think oh yes i may have i may have mentioned it and that's why it came back up in into my head yes i think i mentioned it yes yeah you asked her if she read it but she had i asked her if she'd read it that's right okay um so i was just opening my uh lecture to make this change so i don't forget and uh i want to show you what comes up here uh here we go so this is a slide on neutralizing antibodies right defense neutralize virus particles blah blah blah not all antiviral antibodies neutralize infection then i never go any further i never tell them there's no you know the next slide is a neutralization assay then there's an experiment about how you can uh protect um why doesn't it move ahead there you can protect animals against polio with it passively but i never say so now i'm going to add some slides here to do that yeah so i i have slides in immunology about the five functions of antibodies um but it's really all about neutralization a little bit about a couple of the other ones and the other last ones exist and i feel like that needs to change a little bit actually i do have some more here let me just pardon me for showing things i'm sorry guys i do love to talk about optimization so here i i show different ways that antibodies can neutralize not just by blocking attachment but endocytosis on coding and so forth and then i do have look i have adcc brienne i have one that's good non-neutralizing where the antibodies the here it's an infected cell the antibody is binding to and the nk cells are causing them to die it's good good stuff there's one but i'm going to add more so that's fine you should make sure to talk about optimization that is still one of my favorites from when i was an undergraduate in my undergraduate immunology class because i still have my first exam and i got it wrong on the exam because i remembered the analogy the professor taught but i didn't remember what it meant he said that optimization was like putting butter on something um it was a coating something to make it more likely to be eaten and to make it look more tasty and so my definition of optimization was butter excellent that may that'll make you remind remember things won't it exactly yes all right i have two pics uh the first is an article sent to me by jeff who thank you jeff for sending this again jeff is who is our fundraiser and this is um in medium by ingu yun md the provincetown cove data is actually good news if you're vaccinated and it's really good it's a really nice explanation of why the data uh are not as bad as some are making it it's uh we're hearing nothing but bad news stemming from the recent outbreak of covid in provincetown the majority among fully vaccinated people the war has changed cdc has has said as they issued the report on the provincetown outbreak or as they say a town in barnstable county ah this is the paper this is the mmw's it's provincetown in barnstable county on the surface it looks frightening nearly a thousand cases have been reported from a two-week pa period in provincetown 75 fully vaccinated seven hospitalized viral load you know we talked about this higher higher this and look at this the cdc equating viral load with infectivity is now recommending so this person gets it this person gets it the problem with this messaging is that it increases the fear in vaccinated folks when that fear is unfounded and it sends a message to the unvaccinated that vaccines aren't working which is completely wrong and then the author goes on to explain why there's a different way to interpret these numbers he said he or she says it's not a controlled study it's a report from a period when 60 000 mostly gay men descended on a resort town to pack themselves into poorly ventilated bars and clubs every day for several days no one was wearing a face mask um it rained a lot most people were indoors how do i know this i was there i spent 99 of my time outside but i had to go indoors so he he or she says it's it's an exceptional circumstance in an exceptional location then he goes through the numbers and basically says you know most of these people were vaccinated yeah b-town p-town has an extraordinarily high vaccination rate 95 and he says and they're apparently a as a community very uh sort of community health conscious yes they are he says the numbers tell me vaccines are working which is what we anyway it's a really well-written article so i like it thank you jeffrey uh yeah i saw uh i saw uh uh a pbs newshour uh spin on this from ashish ja dean of yeah public health at brown i always like his reports and he basically said the same thing uh you know barcelona county p-town did an experiment for us okay and first of all there were 60 000 people there and only three or four hundred i think it's up to 800 now uh covet cases okay bill here's a line from the what about their severity yeah right wild here's a line from the article what about the possible increased transmissibility of the delta by vaccinated people well first of all no one knows if this is actually true even cdc questions about the interpretation of their data in the very same report that triggers the warning so i love when i read measured articles that don't try to scare you very good all right the other one is an opinion piece from the times today a guest essay i was the architect of operation warp speed i have a message for all americans from alex azar he basically says get vaccinated folks it's not a political thing i'm really proud of these vaccines you know i helped direct all the development and funding and so forth and my he's a republican of course he said you know some of my colleagues are making it a political issue and that's just wrong just get it i think it's great i wish uh more people from that party would do this he says the vaccines could be a victory lap but they're not treating it that way they're shunning it so it's great i really like this i was never a big fan of of his i thought he said things that weren't right but this is the right it's really important that it's really important that a whole bunch of people that we have never been fans of come out and do the same thing yes more people we thank them for doing it yeah for sure we have a miracle take advantage of it we have two listener picks from jake hello twivers been listening for over a year now the information you supply is interesting and welcomed knowing your group's love of space i have a pick for you nasa keeps a database of the spin-off technologies that come from the space program they update it every year and i thought you might enjoy it very cool this is always useful stuff right stuff that we get from the space program excellent very nice we need this for science right yeah this is awesome this is science but biological science and peter writes dear twiv team i came across this telling of the story of industrial melanism in peppered moths in the style of a children's book but carefully avoiding anthropomorphism and peter provides a youtube link thought it would make a good listener pic pick this is from the atomic shrimp channel they have a fairly eclectic mystery mixture of interesting videos and the description is this is a story i wrote a few years ago about bernard a moth whose life was quite extraordinary in a way that he would never know isn't that great i started watching this youtube about bernard it's quite good i didn't have a chance to finish it before the show started but it's yeah definitely worth checking out and that is epitope 789. i'm sorry i mean an episode i just love that that kid did that i still i do too so kathy you know right some kid yes i heard yes her grandkid asked her what epitope is this i wonder how old the grandchild was it's brilliant i thought she said but i don't remember this is episode 789 you can find the show notes at microbe.tv slash twiv send your questions and comments twiv microwave.tv if you like what we do support us please and support our our venture going forward a new studio so we can do more science communication microweb dot tv slash contribute kathy spindler is at the university of michigan in ann arbor thank you kathy thanks this is a lot of fun brianne barkers at drew university bioprof barker on twitter thanks brianne thanks it was great to be here rich conda emeritus professor university of florida gainesville currently in austin texas thank you rich good thing always a good time i'm vincent vrakaniello you can find me at virology.ws i'd like to thank the american society for virology in the american society for microbiology for their support of twiv and ronald yankees for the music this episode of twiv was recorded edited and posted by me vincent racquiniello you've been listening to this week in virology thanks for joining us we'll be back soon another twiv is viral [Music] you

Channel: Vincent Racaniello

Views: 23,836

Keywords: virus, viruses, viral, virology, COVID-19, delta variant, SARS-CoV-2, vaccine, alphavirus, non-neutralizing antibody, Fc receptor, transmission

Id: XqFySCWT_x8

Length: 108min 59sec (6539 seconds)

Published: Wed Aug 04 2021