Vax Science: An Interview with Dr. Sandra Chang

[Music] [Applause] [Music] you have to realize that even for the flu vaccine there are still people who are vaccinated who get sick but they don't die you know because of the vaccine that they receive and so maybe this is a very similar story here we're going to have vaccines that may not completely protect you against infection against all strains of covid but it may protect you against severe disease hospitalization and death aloha i'm robert perkinson i'm the coordinator of the uh better tomorrow speaker series which is a joint venture of uh the hawaii community foundation and kamehameha schools and today we're going to be talking about the science behind the covid vaccines both those in the pipeline and especially those that have been approved and are actively being used in hawaii our guest today is uh medical school professor sandra chang she's a microbiologist and an immunologist by training she's worked a lot in vaccine development herself for malaria and many other diseases she's a professor in the department of tropical medicine medical microbiology and pharmacology and she is the co-chair of the state department of health's vaccine medical advisory working group um thank you for joining us oh thank you for inviting me so i thought that it would be useful for people to [Music] have for those who want it a deeper scientific understanding of vaccine science generally and all of the different types of vaccines that are in the pipeline as more you know it's two mrna vaccines that are approved and used so far but others are likely to be approved um before we really get into it however i think it's worth for a moment just reviewing what we know so far about the safe and efficacy data of the approved vaccine a proof vaccine so first what can you tell us about safety how is it going now that we're getting a lot of shots in arms yeah so you know they've been continuing to monitor the safety and by they i mean the cdc and the fda they have a variety of ways that they can do this and of course people have been concerned about anaphylaxis because that's been the most severe side effect that has been observed and they've looked now for both the pfizer and the moderna vaccines at many more doses in arms and have looked at the number of cases and so for the pfizer vaccine they've seen a total of about 50 cases per about 10 million first doses of the pfizer vaccine so that gives us a frequency of about five cases per million doses of anaphylaxis for moderna they've seen 21 cases and about seven and a half million doses administered so less so the incidence has gone down yeah 2.8 cases per million so as they look at more you know individuals they can get a better read of how many cases they're really seeing in the population and it does look better still a little higher than most other vaccines but not tremendously higher just slightly higher of course they're monitoring very closely as you know people who get vaccinated are monitored for at least 15 minutes and if they have a history of severe allergies they are monitored for about 30 minutes after they receive the vaccine and still in the united states no fatalities associated with these incidents of lexus none of them have been you know there are always these anecdotal cases that come up but when all of the cases have been followed up they have not been able to directly attribute any deaths to the vaccines or to anaphylaxis caused by the vaccines yeah so just to reinforce the basic math for people who might be worried about anaphylaxis by contrast um so if they're if the weight per million is what did you say about five or less for the ladies yeah two and five about 2.8 for moderna and about five for pfizer so by contrast if the covid case fatality rate is say 0.5 percent maybe it's a little bit

lower than that it depends on your age group yeah that's 5 000 cases per million yeah um so i do hope people do the proper comparison yes risk and realize so much greater with covet just like flying is safer than driving drunk getting a covered vaccine is a lot safer than getting coveted it's not even close [Music] um what about efficacy we have the you know the phase three trial results for the two approved that had greater than 90 efficacy which is astonishingly high is isn't that astonishingly high for a vaccine well i mean there are other vaccines that are that efficacious as well but um it is on the high end of the scale and certainly better than we had expected yeah and is that number to what extent are we getting data from real world mass vaccinations in terms of um covid transmission they're monitoring it but i haven't seen um numbers you know in terms of percent efficacy with routine use of the vaccine it's just from the clinical trials yeah there's the only place i know that's closest is israel that has now vaccinated the greatest portion of their population and the cases have plummeted yes even despite the fact that now it's the more contagious variants that are dominating their caseloads so that's ironically kind of double doubly good news yeah um hopefully they will get them to palestinians as well that's true um okay well i thought it might be helpful for people to go back in time and sort of understand a little bit about the development of vaccines how far back does this field go it goes back pretty far um so the first practice that was similar to vaccines was a process called variolation and that was in relation to smallpox and this was back in the 1500s this is cow pox smallpox i mean but you they were is this the one where they were using cowpox no no no okay not yet so what they were doing was they were taking puss or dried scabs from individuals with smallpox and introducing it to naive individuals who were at risk of getting smallpox either they were putting it in their nose in their the nearest of their nose or they were puncturing the skin and putting it on the skin and so that's the process called variolation pretty crude but effective um and so this was happening mostly in in asia and then europeans when they traveled to asia observed what was happening and it seemed to have a benefit so this was taken back to europe when they had their own smallpox pandemic there and they started doing the practice of variation of course you know that was gradually improved and so um edward jenner was the first uh physician who introduced the process of vaccination and that's where cowpox i see although interestingly um there's still some controversy as far as what the true origin of this vaccine was because there are two diseases that are very similar and that's cow pox and horse pox and it's possible that the uh broadly used smallpox vaccines are actually derived from horsebox but uh they're they're closely related yeah and so was cowpox vaccine used in mass inoculations or was polio the first where kind of everyone no it was used in mess i mean um so smallpox inoculation was used systematically i would say to eradicate smallpox you know and so that is the first disease infectious disease that has been eradicated yeah um and yeah and polio was close it's getting there i mean there's still a few pockets a few countries where they're seeing cases of polio but um for most most of the world it's been it's disappeared for a long period of time yeah and the original polio vaccine was an attenuated virus vaccine um so there are two types of um polio vaccines so there was an attenuated virus vaccine and then there is the inactivated virus vaccine and so um you know they're used in different ways um the attenuated one is used in more uh in areas where there is a high level of transmission and they need to control the disease and prevent transmission so very often because it's good it's more effective yes it's a little bit more effective but there are dangers associated with uh using a live vaccine in a population and so the inactivated vaccine is used in areas where you just want to do mass inoculation and protect the population but there is no really high risk of of getting polio in those populations you know you just want to eradicate it i was interested to see that there's one of the vaccines that's in trials is an attenuated or an activated vaccine not not one of the ones i don't think it's phase three it's an inactivated vaccine yeah oh okay there aren't so much what's the difference um sars vaccines in development no live attenuated sars vaccines involved only inactivated so inactivated are not tell me that they're killed by chemical processes they're just treated with chemicals um that inactivate the virus so that it cannot replicate but they're still able to induce immune response that's protective and so the one in china there's a vaccine that's been developed in china which is a inactivated vaccine i see but the ones that look like they are in late stage trials now are um the protein subunit vaccine is another one okay so that's nova vaxx is the one that's furthest along that's a protein subunit vaccines and then there are the adenovirus vaccines and those are really interesting vaccines because okay tell us about those that's like johnson and johnson and astrozenity yeah that's pretty good so those vaccines are interesting because even though they're based on the adenovirus it is a non-replicating adenovirus so the virus carries the spike protein from the sars by virus so just one protein from the sars virus and carries the gene for that into the host cells and then um the cells make the spike protein release it into circulation and you develop an immune response to the spike protein that way that way but the interesting thing about these viral vaccines the adenovirus vaccines is they enter into the cell but they do not reproduce and so they're kind of like a viruses themselves yeah right and so it's not capable of producing an infection a viral infection in hosts so how does the yeah why does why do we humans not react and kill the adenovirus before it has a chance to insert the proteins and get them in production well for one thing it's a relatively high dose that they are administering so while you may be inactivating part of the inoculum um enough of it is getting into your cells to produce an immune response are they also choosing viruses the that are that we tend to be naive to or yeah they are so one of them is a chimpanzee uh form and then the other one though is more closely related to the human um adenoviruses and the sputnik vaccine is very interesting because it consists of both the chimpanzee and the other adenovirus 26 which is more closely related to the human ones and so the idea so it has two two viruses that are entering two different ones right interesting and so if you develop immunity to the first one it's not going to protect you against the second one that goes in and so it has a better chance of inducing the immune response oh wow yes is that a lot more yeah i mean theoretically it sounds like a better strategy but in reality i think you know both types of vaccines both the abnormal 26 that's used twice as well as the um adeno 5 and the admiral 26 combination they both induce a very strong immune response and pretty good efficacy and do they require adjuvants like the novovax vaccine or not okay so tell us about the protein subunit technology and how that's different from those we've been discussing so the protein subunit technology is a little bit different it involves formulating a protein in a way that allows it to be immunogenic to induce the immune response and um it does include an adjuvant the adjuvant that's used for the novofax is their own matrix m protein which is sort of a lipid composition adjuvant that enhances the immune response to the protein subunit spike protein itself and so usually when you uh make a protein subunit vaccine you do need to add some kind of an adjuvant and so this is the one that is being used by novofax and so this one delivers the the sars cove to proteins directly you're not manu it's not calling up on the cell it's already pre yeah pre-made it's being injected and then it's taken up by the cells of the immune system and present it to the immune system in a way that induces a good immune response the fact that there are so many different approaches and presumably these vaccines are also using different parts of the spike protein or do they tend to damage it they're pretty much using the same spike protein because that's the sensitive target for the virus that is required for viral entry yeah so if the virus evolves to have to be vaccine resistant it it probably it won't matter that there's so many different vaccines targeting it it should develop immunity to all of them more or less well you know there's of course there's a lot of discussion right now about that whole issue because of the variants that have emerged already in uk as well as in south africa and so you know there is a real concern that the current vaccines may not protect against these emerging viruses and um you know we don't know everything at this point in time but so far the data seems to indicate that at least for some of the vaccines it looks like there is good cross protection against the mutant forms now you know there may be some disease some mild disease a moderate covet infection of individuals that are infected with the variant strains but so far it looks like there is no severe disease there are no hospitalizations and no one has died who has written personalities right yeah uh-huh yeah another another amazing metric of vaccine efficacy so far i i read a few days ago is that they're among vaccinated individuals there's not been a single coveid verified covet fatality yes it's pretty amazing i mean you know we had no idea that it would work as well as it has and you have to realize that even for the flu vaccine there are still people who are vaccinated who get sick but they don't die you know because of the vaccine that they receive and so maybe this is a very similar story here we're going to have vaccines that may not completely protect you against infection against all strains of covid but it may protect you against severe disease hospitalization and death so is it is it possible that this enhanced efficacy has to do with the mrna technology um but they're seeing it in in the other chapter platforms yeah okay um well let's turn though to the pfizer and moderna vaccines and i wonder if you could sort of walk us through the development of this mrna technology that people have been talking about and promising drugs and yeah vaccines for some time but this is really the first time it's being successfully used yes well it is a relatively new technology it's the newest technology of all that have been tested so far um and so you know it appears to be very effective at inducing a potent immune response um again it has the advantage of being safe because what happens is the messenger rna is in encapsulated in a lipid part particle or bubble and so this lipid particle carries the messenger rna that encodes the spike protein into the host cells and then it enters the cytoplasm of the whole cells but it doesn't go into the nucleus and that's what makes it very safe because it has no um mechanism for inserting into the host dna it remains in the cytoplasm it's very rapidly turned over so there's it's just around for a few days and the whole cell will make protein from that messenger rna it'll prime its immune response and then eventually the messenger rna and the protein will be cleared from the system so one of the challenges to developing mrna treatments was the fragility of the mrna and figuring out how to deliver it to the cells right so is so was it the lipid bubble that's as much of a breakthrough here as well right i think so yeah what what worked this time just protects it again so so the reason why it's so unstable is because in our cells within our body we have these nucleases or proteins enzymes that break down rna very very efficiently and so what the lipid particle does is it protects it from those proteases and then it fuses with the cell releases it into the cell now the cell also has proteases but there is enough time for the messenger rna to be synthesized into protein before all of the messenger rna is degraded so um yeah that's the base the basis for these messenger rna vaccines and in terms of the challenges of the super cold temperatures especially for the pfizer bioin tech vaccine um is it the mrna itself that requires super cold storage or is it the lipid nanoparticle that well i think it's the combination certainly the mrna is more stable at low temperatures but the whole formulation is probably has a longer half-life at lower temperatures and what happens if it warms up you know i i haven't really thought about that but i can imagine that you know the lipid would degrade and the messenger rna would be released and be never made to the cells i see um there's at least the last i looked at a list of ingredients the number of ingredients in the vaccines is quite small but you know nonetheless people hesitant about putting new substances into their bodies are concerned about what's in it so what can you tell us about the other both the you know you've talked about the um way that the mrna is broken down and removed and doesn't enter the nucleus so that's how we know there won't be any kind of genetic changes wrought by the vaccine um the lipid nanoparticle i guess is also broken down and metabolized quickly yes and then what are the other ingredients and how common are they on other medications or vaccines yeah so um all of the components you know are pretty commonly found in medicines or cosmetics or other products that we get exposed to every day much of it is salts that buffers the ph of the particle itself keeps it stable and we also have a number of different types of lipids that make up the nanoparticle and so those are the other components and then we have the messenger rna now the lipids include one particular molecule which is called polyethylene glycol 80. and this particular one is the one that they suspect is being associated with the anaphylactic responses in a few individuals and it is related to polysorbate which is also a molecule that they want to be sure that you don't you're not allergic to because those are two structurally similar compounds and so um really the phospholipids and the polyethylene glycol are pretty much the only other components other than salts and messenger rna okay i have a more and more people um as the weeks go on will receive their vaccinations um i'm one of them i've i signed up for the bio and tech trial and i i got unblinded the other day and found out that i much to my relief that i did not receive a placebo so i'm fully vaccinated but i was kind of surprised to discover that the trials weren't designed to assess whether or not vaccinated individuals might still be transmitting virus so how how would that work why is it important how could theoretically vaccinated people infect others if they are immune so what what we know the way that the trial is performed is the readout is covid19 symptoms and the presence of the virus by rtpcr so that is what they're looking for in the vaccine trials and so what the trials say is that if you're vaccinated you're protected against developing a cova-19 infection that is associated with symptoms what they're not what they don't know is how many individuals are infected that don't have any symptoms at all because they weren't monitoring everyone in the clinical trial they were only monitoring individuals with symptoms right yes so that's why they cannot say at this point in time whether you can be vaccinated but still release virus if you're asymptomatic um but presumably one would be much less infectious at least i would imagine so right i imagine that would be the case that you would have fueled a virus in your body it seems to be also the i mean it's very preliminary the data but it does seem like infection rates though they're very high are starting to go down in areas where um you know vaccines have become more prevalent and they're looking at they're looking at symptomatic infection they're not looking at asymptomatic infection they are doing some studies i know of one study that's being done in health care workers where they are monitoring individuals for a symptomatic infection who have been vaccinated right and comparing that to the unvaccinated population i think they tested us for antibodies a couple of times in the trial to look for past infection it is the i did come to appreciate just what a massive operation a phase three clinical trial is over the course of being involved in one myself i yeah i had not really realized how many hundreds of millions of dollars and highly trained staff and infrastructure you need especially in so many different places at the same time right yeah um and it's amazing i it's important for people to realize i think that these vaccines have gone through all of the regular steps yes um as they would with anything just it's just been expedited by a so much covid and which means we get to discover fxc faster and um be the fact that they started manufacturing even before they got full results right right i mean they started manufacturing very very early um so when they first got the um the vaccines developed or created i suppose you could say and started testing it in animals they were already trying to start the process of manufacturing clinical grade material that could be tested in humans as well as developing manufacturing capacity for these vaccines so it's a tremendous investment in resources for the companies that were developing these vaccines and of course this was supported by the government by the government too yeah yeah no it's important for people to realize that the corners weren't actually cut no there was just a lot of money spent to speed things up um well another question i had is you know to what extent do we now have data on um the level and the duration of immunity in vaccinated individuals versus infected individuals is there much comparative data that's reliable yet that's just a little bit of data um you know for the vaccines we've only been following them for less than a year now so it is you know not possible for us to say exactly how long immunity will last with the vaccine but it will last at this point at least at least six months probably they're gonna be following them for two years so we'll see in time how long immunity lasts but in contrast for um people who have had covet 19 when they've looked at sort of a correlate of immunity looking at antibody production in these individuals they find that yes some people who get very sick make high levels of antibody that may be able to protect them against re-infection but other people who have just mild cases of covid sometimes don't make much antibody at all so just because you were infected does not mean that you are protected against reinfection and even for those who have been protected for a short period of time um you know those antibodies may disappear over time as well i see so whether you think you've had covert or know you've had covert or not when you can you should still get vaccinated in other words definitely do you think it makes sense for people who've had a confirmed case of kovid to go to the back of the line or maybe receive a single shot instead of two in order to get i think well that's in the door depends on their risk you know if you're someone with a lot of comorbid conditions i would certainly not put it off if you're you know a young person very healthy and you feel like you know you could wait a little bit well it's your choice you can do that as well but you're still at risk of developing severe disease which does happen in young people as well as older people and people with comorbidities so let's talk we've talked some about um you know the extraordinary speed um use of new technologies and success of this this is really the one bright spot that we have in the pandemic how effective and quickly the vaccines have been developed even if they're maybe not distributed as quickly or as efficiently as we'd like um but you know this basic science that's been and what we've learned from this effort should it pay dividends in other areas of vaccine um research like for instance i'm as an as an outsider i find it puzzling that hiv is so difficult to vaccinate against compared to um coronaviruses why is that and and might some of these new technologies help with older diseases or the virus is so different that well you're not comparing apples i mean you know it's possible that a messenger rna vaccine might help in case of in the case of hiv but the problem with hiv is that immunity is very difficult to develop you know for people who are naturally infected with hiv they can be reinfected and in fact they develop chronic infections they don't clear the virus completely from their bodies so in situations like this where immunity is so difficult to achieve even with natural exposure it becomes even more difficult to induce by vaccination and the other thing about hiv is that that particular virus has a very high rate of mutation even in a single individual you can have many many different variants arise over time and so it's been you know such a challenge to develop a hiv vaccine for those reasons and the other reason is that the virus itself hides within the host cells and incorporates into your dna and so you know it has a latent form that persists for many years as well and so it's a really popular to crack yeah whereas by contrast the coronavirus is um it's an acute infection yeah and they also have a these viruses have a mechanism for to slow down mutations right to kind of as they're replicating to double check they haven't made mistakes they do have yeah correction mechanisms that's right and hiv doesn't well not very effective ones yeah it's more error prone how is it that some viruses don't generate any immune response at all like hiv or so little that that some viruses generate so little recognition from the immune system like hiv and in the case of natural infections even though you get very sick in some cases or these difficult infections very often what happens is your immune response does recognize and does produce a response but that response is not protective i know it's just recognizing it but it's not harming the virus in the ways that need to be uh done in order for it to be eliminated yeah and is your own research has been in malaria vaccines yes yes and how is that how is that fundamentally different or similar from the sorts of vaccine researches that we're seeing with well you know there is there is a malaria vaccine right now that's being piloted in areas of the world that have high rates of malaria transmission and it is partially protective against malaria infection but malaria is one of those diseases that you can get many many times within your lifetime and um you know immunity is not very um strong or long-lasting against malaria just natural immunity i think so and there are many different variants of the malaria parasite in circulation so again you know it's similar to hiv in in a sense that the virus has evolved and competed very successfully with the human immune system over time i see and so you know where where do you hope we are in vaccine technology say 20 years for not from now what's you know 20 years ago people were talking about the promise of mrna what are people talking about now that might be over the horizon yeah i think certainly developing strategies that can identify the targets for some of these more difficult diseases is is very important you know if we could just find which components of the hiv virus or the malaria parasite is very vulnerable to the immune system and we can induce the response to those components i think there's hope but i think there's some still a lot of basic immunology that needs to be done on these infections um but then the other side of the coin is just because we have a coveted vaccine doesn't mean that we've reached the end of the game you know it's only as good as as many people take it and as you know you know if people don't get vaccinated if we don't reach a level of herd immunity that pull protects the population then these vaccines will not help us to control the infection to reduce the number of cases and to eventually eradicate the disease and so i think one of the biggest challenges is to achieve the level of immunity that is necessary to really end this pandemic it's also worth pointing out i think that the the more covetous circulating globally the more chances the virus has to mutate in way and and every once in a while one of those mutations is not a friendly one that's right that's right um okay well let's let's talk about the efficacy and hesitancy um so i you know in my conversations with people i've had questions a lot of questions that fall into two categories one about people with various pre-existing conditions like um who are immune compromised who have cancer what is the advice for people who have ongoing health challenges about whether they should or shouldn't get vaccinated well i think it's comes down to your own personal decision about your own risk of being infected and your own risk of developing severe disease so far even though immunocompromised individuals were not deliberately included in the trials it does appear that they are able to make an immune response to the vaccine and be protected hopefully against the disease and so you know i think the recommendation is that even though you may have a chronic health problem or you may have cancer or you may have autoimmune diseases but there's no reason why you should not get vaccinated it's no guarantee that you'll develop a strong enough immune response to prevent infection but it may be sufficient to protect you against severe disease and save your life yeah and again it seems like the if one compares the possible risks of the vaccine to the known risks of covid at least in all cases that we know of so far covid is entails far greater risk in in any in any age group or any demographic that's been studied at least as far as i know what about groups of people who were intentionally left out of the trials pregnant women lactating women um extremely elder you know very elderly individuals over the age of 90 and so on like are there any is the recommendation across the board that these groups too should be vaccinated i think yes they are recommended to receive vaccines for pregnant women um there's no indication that at least the vaccines that we have approved so far uh provide any risk to the woman in terms of the pregnancy as well as to developing fetus and so it's felt that you know pregnant individuals should be vaccinated um and i think there's some preliminary if memory serves there's some preliminary evidence that immunity may be past some some antibodies may be passed to the infant from the mother as well that's the normal situation that you do yeah have there is placental transfer of antibody that's right and that would be true with vaccine generated antibodies as well as that's true yes yes [Music] um okay well are there any did you think we would be here uh it's almost a year ago it's almost exactly a year ago i think that i started reading in the newspaper about um this new outbreak and it has been dominating our news in our lives for a year yeah um how has the development of the vaccines gone compared to what your expectations were a year ago well it's certainly been better than i expected i mean i it's been faster than any other vaccine that has been developed and in terms of effectiveness it seems to be quite good um of course you know it's uh it's a game against the virus right now for us to be able to vaccinate people before too many um more severe variants emerge and spread within the community so i think uh it's a race it's an arms race and so you need to get those vaccine in those arms and and you know help to get rid of the virus and prevent the emergence of more serious strains of the virus right it's been a hard year but it is it is very nice that we at least have some hope of moving forward even though it involves a lot of logistics and difficulties but and i want to thank you for all the work that you've been doing oh you're welcome um on recommending vaccines and vaccine research and vaccine education that's really valuable i know that all of you at jabsom and you yourself have been working around the clock for a very long time now thank you well we're very happy to do whatever we can to help the community provide them with the information they need to make good choices and you know i encourage everyone to seriously consider getting vaccinated when it comes to their time me too okay thank you very much dr chang nice to see you yeah and have a nice night good night [Music] you

2021-02-26 21:04

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