With a focus on protecting children, infectious disease physician Monica Gandhi, MD, MPH, examines COVID-19 in the context of past pandemics while also illuminating its unique challenges. She presents the data on what works to keep pediatric, senior and immunocompromised populations safe; explains when and why “waning immunity” occurs; and offers a look at what’s to come, from new vaccines and treatments to everyday precautions in a world with endemic COVID.
um so you know I actually just wanted to mention I do this before. Any SARS covid to talk covid talk is that we have had two other corona viruses that cause pandemics in the past. They just were never this bad. So SARS was another coronavirus that came out in 2000-2003. It caused 80 100 cases in 774 deaths around the world. And it came from a horseshoe bat, went through a palm civet and came into humans. And we also had murders which was another coronavirus that did this. Also a very limited pandemic in 2011. Um And uh the reason I even mentioned MArs is this is when the M. RNA vaccine started getting developed. They actually started developing M RNA vaccines for MERS. But then we didn't need it because it was so limited. And then you know everyone knows the history of covid 19 that it was december 31st 2019 when the W. H. O. Got alerted to this new coronavirus, they figured out it was a new coronavirus just a week later. And it was a pandemic as of March 11th 2020. And we think it came from a bat but we don't know what came after that. And there's been a particular hallmark of COVID-19. That's been really completely different than other pathogens that we were fearful that would cause a pandemic. Which is that somehow Young Children in general were spared severe effects of COVID-19. And it has to do with some path of physiology mechanisms that I'll tell you about in a minute. But for example in England Out of 12 million Children who lived in England less than 18 Of all the deaths in England um from COVID-19 about .8 Were in those who are 0-17 years old. And that is actually and that is not true of older adults of course. Um where the rate of death is much higher. It's about 1% before we had good treatment. And here in the U. S. The CDC estimates that Um you can see that under one year 248 deaths. 0 to 17 total is 962 Death. So what that means is that that becomes basically less than .1% of all our deaths were in 17 and younger. And in fact they just downgraded the number of pediatric deaths about a week ago. Um what happened is they had a coding error and so um they had overestimated the number of deaths in Children, luckily it was 25% less. Um so vaccinations. Adults certainly protect Children. We know that from studies in Israel but we had more of a delta surge in the U. S. Among states where unfortunately adults were not as high a vaccinated. So less than .1%. And this is also true of the data here in California. Less than .1% um of deaths were in 017. So .001. So why do we think Children are spared? Because that's not true of measles mumps, diphtheria pertussis, um rubella, so many other childhood diseases. It there are two possible mechanisms. I think this is the lesser of it. One that got um talked about early on was having fewer ace two receptors in the nose um in the nasal cavity. And that's what what brings in the covid virus. That's true in a way. Um but and it's it's true of younger Children but I think it's more this and essentially our innate immune response is so involved in the path of physiology of covid that actually um uh we use of course the XM episode in severe cases of covid because it's really the immune system gone out of control. It. The innate immunity of Children is different. They basically have higher levels of isle 17 of interferon gamma and essentially prevents COVID-19 from going down in the lungs. So it just is a particularly a very blessing really that Children have this these innate immune defenses that have prevented them from getting very ill from covid. I now want to turn to school closures only to tell you for as an example that in the history of all pandemics, We actually never closed schools like we did um in COVID-19 at least here in California for example. And what I mean by that is even during measles break break break outs in 1892, school closures were always considered something that we had to do as a last resort malaria um diptheria. It was a very last resort in the history of schools just because schools is such an important place for Children and if they were closed, they were closed for really short periods of time. And in the 1918 pandemic, which was a very kind of created the pandemic playbook. Um this wasn't even an infection that differentially spared younger Children like COVID-19. But in influenza it was very political where the schools got closed new york actually absolutely refused to close their schools. Um So did Chicago and soda New Haven. And that was because they said schools are a place 750,000 of our Children, for example, who go to school living in tenements, low income tenements. So we need people to be at school to make sure there's no abuse in the home to make sure there's food for them. And so even though they were told by public health authorities Um to close their schools, the health commissioner of New York said absolutely not and they did not close their schools in all the progressive cities um in the United States in 1918. Um and this is actually the article, it's really interesting, which explained, you know, why they refused to essentially it was because rules are places of food and learning and safety. Um and these are just some historical articles, I'll send you all these slides, but I thought these were really fascinating that it was really the progressive cities that wouldn't close. Um And so in other schools like in Ontario, they didn't close them, but they did things like teach hygiene. Uh this is all the kids learning how to blow their noses um and they did a lot with ventilation. So outside air um was really used Berkeley close to schools for four months and then they reopened them, but they used a lot of outdoor ventilation and you can see here our kids napping in blankets um because ventilation is such a powerful strategy for respiratory Um and sometimes they use mass because it wasn't actually a universal, it was much more about ventilation and this was where school nurses were born. Um it was in the 1918 pandemic and the concept that you should stay home when you're sick. Um and school lunch programs were really heightened during this time. As you know, we did things differently in the covid pandemic um School closures actually happened globally and they are now currently 400 million Children still out of school worldwide. Um The schools in Uganda just opened up three weeks ago and unfortunately half the girls didn't come back. So concern for girl's education and in fact um UNICEF has been, you know, sort of Writing about this continuously really since the summer of 2020, how hard it's been in the low income setting for schools to be closed and how this could step back Children for a long time. Um, in the United States, our school openings were very political, but the opposite way um, California Oregon, Maryland Washington and hawaii were the fifth five schools that kept their five states that kept their schools closed. The longest in California in the public school system was 50 out of 50 in reopening schools. We reopened up and followed 2021, so it was At least widely. So it's pretty much 18 months of school closures with remote learning. Um, so, um, so I did write a lot about schools and, and especially after the teacher vaccinations became available because we know that they can have such impacts beyond that there was great um, uh, studies that happened from the CDC onward, large studies that showed that schools weren't really major places of transmission of covid 19, like I will say that like hospitals, they had a lot of mitigation procedures in place. Sometimes they didn't, but many times they did. And the mitigation was that were used for masks ventilation testing at times. Um, and distancing and really, all these school studies showed that cases in schools were really highly correlated to case rates in the community, that most of the cases came from community exposures instead of there at school. Um, and, um, so, You know, definitely the country did reopen at schools essentially in fall of 2021 everywhere including California. And um we wrote this article in the new york times in june of 2021 saying how important it was and suggesting mitigations but suggested mitigations that would be peeled off as hospitalizations fell. So masks until there were 10 hospitalizations over 100,000 people. That actually was the criterion that was chosen to drop masks Um by the c. d. c. just like um on February 24 and ventilation. And we didn't actually recommend mass asymptomatic testing and the policy lab at Children's hospital pennsylvania Reiterated those guidelines in January 2022 saying that masks the symptomatic testing did keep a lot of kids out of school. Um We all know that there have been mental health effects of the pandemic. Um And uh including those school closures. Um And what the California DPH now recommends um is really the single most effective strategy to reduce transmission in schools is vaccination. Um And vaccination of teachers and adults and um student there is a student vaccine mandate as of september of 20 22 in California. Um I'm not sure if he'll be enforced. Um only New York and California and California have that. Um There was masking in schools until um this last month because that's when the CDC discontinued masking in K. to 12 schools based on hospitalization rates in the community and outdoor masking actually has never been shown to be um uh needed for reducing outdoor transmission since ventilation is such an effective um it really is amazing how much adult vaccination protects Children. We really saw that Through the Delta Surge, Children, hospitalizations were much higher in places with low rates of adult vaccination in July through October 2021 as delta surged and went through the country. And that was the south and south more of the south and Southeast states. We had high rates of vaccinations in here in California. Um In terms of quarantining, there was just a report On March 31. So just a couple of days ago from L. A. times saying that nearly half of l. a unified school districts have been absent this year. Students have been absent year this year. The difference between L. A. Unified school District and SAn Francisco Unified School District is L. A. UsD does mass asymptomatic testing, but SAN Francisco Unified School District does not do that as of september 2021 Based on the policy lab recommendations. Um so it definitely keeps Children more out of school to do mass asymptomatic testing because of quarantine. That disproportionality was more about actually 59% of African American Children have been chronically absent for about a year for half this year. Quarantines remember came out of this concept of keeping ships um for a quarter for 14 days off in the black in black, basically the bubonic plague. Keeping ships away from the Italy mainland and they'd have to sit there for 14 days. But but the CDC really rights um in an article about quarantines even prior to this, this covid pandemic that all the benefits of quarantines have to be weighed against the harms in turn including public interest, individual rights, socioeconomic, ethical and political issues. Um So anything that reduced quarantine could keep Children in school longer. And there was a mass test to stay program that was enacted over the omicron surge in massachusetts. They did a massive test to stay program and showed that very little transmission again was occurring in schools. And as a result of that, that's what really strengthened the policy lab chop recommendations not to do asymptomatic testing in schools. Okay. I want to turn the vaccines because I think that when we get to the confusion about child vaccines, it really has to do with antibodies versus T cells or B cells. And I feel like we always have to remind ourselves of the immune system that essentially what is happening with the immune system is that vaccines will produce antibodies they absolutely will. But those antibodies go down after time and in fact the different variants, antibodies don't work as well against those variants. For example, omicron variant has 32 mutations across the spike protein. So we saw a lot more mild infections because antibodies protect you up in the nasal cavity with I G. A. We saw a lot more mild infections even with vaccinated boosted adults during the omicron surge. Um But we didn't see severe disease among the among the vaccinated except for those who had not been boosted or especially when they're older meaning those at risk for severe breakthroughs. And that really had to do with our T. Cell and B. Cell immunity. T. Cell immunity is created by all the vaccines. It's been measured and T cell immunity protects us against severe disease. And B cells are produced by the vaccines. They've actually you know biopsy people's lymph nodes not Children but adults to make sure that in the germinal centers B cells are being formed and they absolutely being formed and remember what B cells do. They will produce antibodies in response to a stimulus seeing another variant in the future. And they'll actually produce antibodies that are directed against that variant. Um So that's the amazing thing about adaptive immunity. It's why actually there was a study on omicron specific vaccines and they didn't macaques at least and they didn't do anything different than the old vaccine against what's called the Wuhan uh h you strain because essentially just bolstering your B cell immunity it will produce antibodies directed against what it sees in the future. So remember all the vaccine trials because we now have nine vaccines that are in common use. Um I will say that only the top three or in this country of course Moderna Pfizer and johnson and johnson. But we have nine vaccines. The six here are all spike protein vaccines, they involve the spike protein in some way. Moderna and Pfizer involved the um the M. R. N. A. Uh the R. M. RNA vaccines that code that make you code as the host for a piece of the spike protein. And then you raise a strong immune response. And johnson johnson is A. D. N. A. And no viral vectors. So it's a D. N. A. Inside an adenovirus that brings it in benignly. Then you make the D. N. A. Into M. R. N. A. And then you make the spike protein and raise a strong immune response. These three at the bottom. Also our spike protein vaccines Astrazeneca and Sputnik five are also at no viral DNA vectors. And Novavax is very traditional. It is a protein combined with an adjuvant just like diphtheria pertussis, tetanus vaccines. There are some hesitant vaccine, hesitant people who are waiting for Novavax because they're uncomfortable with the genetic material in these other vaccines even though it's very safe. Um and Novavax filed for approval For their vaccine in this country. Um on 21 January 2022 you can see by column for that all of the vaccines produced strong T. Cell immunity. I think that's amazing because we never measured T cell responses to measles vaccines or to theory or protesters because we didn't have that technology. But all of them in the phase 12 trials raise strong T cells. These were not conducted in Children. These initial phase 12 trials but there's no reason to think um Children aren't raising the same cellular immunity to the vaccine. And so actually in the in the clinic original clinical trials and adults, you can see by the yellow column that there was almost 100% protection from severe disease because of the T cell immunity that was raised As our antibodies come down. There are people who are at risk for more severe breakthroughs. There are people at risk for moderate or mild disease and that has been happening. But in the original trials, that's how strong T cell immunity was um to cause almost 100% protection against severe disease. And this is true of the three um what are called whole inactivated Varian candidates. There's the covax in product which is the top made in India and Sinovac and Sinopharm. They also raise T cell immunity. I will say just as a comment, those Sinovac and Sinopharm vaccines which are widely available in china. That's where they're made. And they have um given them too many places in the world are probably the least effective of the nine vaccines that I just told you. They really do need three doses which the World Health Organization was very clear about. Even when they were protesting boosters for the rest of the planet because they wanted more vaccine doses to be given out to people haven't gotten their 1st and 2nd doses they're recommending three. So even Children need three doses of Sinovac and Sinopharm. Okay. And so the reason that we know that we have held up against severe disease protection even through a micron is again this T cell immunity. In fact there's many recent papers about seven that shows that all your t cells developed from the vaccines are cross reactive even against a micron with its 32 mutations across the spike protein. Because T cells form such an in breath response across despite protein, there's about 100 T cells that line up across the spike protein. They didn't even if you have 32 mutations, those 67 T cells are still there to protect you. And then the same thing with B cell immunity which I'll talk about in a minute. This actually shows you that through the delta surge. It was only those over 65 that had a reduced protection from hospitalizations. Um actually up to the age of 60 for the hospitalization protection from two doses was intact. So you saw this argument happening with the FDA and the administration and eventually they approved boosters for everyone. Um But the FDA originally at least the advisory committee only wanted it for older people over 65 you can see the same argument happening with the fourth dose. This is the paper that I really want to um have you read at some point about B cell immunity because it's pretty amazing. But essentially what this paper shows us is that B cells if if you take a little time and your antibodies go down with time um uh you know, your antibodies will happily come down with time. That's just what they do. It's really unfortunate. But you can't keep all that protein your blood. If B cells seek another variant in the future, they will absolutely produce um antibodies directed against that variant. So who do we decide who needs boosters? People who cannot wait to produce those neutralizing antibodies that will take about 3-5 days to make antibodies. And there are some people who cannot wait to make those antibodies and those are immuno compromised individuals and older individuals who are more risk for severe breakthroughs. So to talk about the variants. Um but I want to give us time. So I'm gonna go through this a little more quickly so I can get to the child vaccines. The variants you all knew was alpha and delta were the biggest in our country. Beta and gamma did not come to the United States very much because they weren't more transmissible. But of course alpha and delta had a huge impact in this country. Are Macron is the latest. I already told you about how many mutations it has across the spike protein, but it has about 51 across its entire surface. There are estimates from Uh from a modeling um from a modeling a modelers basically epidemiologist at the University of Washington that 75% of the world's population has been exposed to a Democrat. I don't know if that's true. Johns Hopkins also model 75% of Americans, but another model shows 45% of Americans. I don't know how many people in the United States saw a macron, but a lot of people did through our last surge. A lot of the planet saw macron through our last search. What that did was create a huge amount of immunity across the entire virus. It was actually less virulent. It was less likely to infect lung cells. In fact, there was a recent paper in Jama pediatrics from just two days ago because there was initially some confusion that younger Children, less than five, we're getting more sick with omicron than Delta. But a really nice analysis in Jama pediatrics showed no, they were less sick from a micron then Delta because it really doesn't infect lung cells as well. It didn't mean that it didn't cause a lot of suffering because it was so transmissible that those who are unvaccinated or older and at risk for severe breakthroughs did get sick during the american surge. It did create a lot of immunity. And right now the entire planet is except for china is actually transitioning to endemic management of this respiratory virus that probably would not have happened if we didn't have a microphone if you want to put in a plug later for kovacs in and the only reason I'm even mentioning this kovacs in product, it is a whole inactivated Varian which shows you the entire virus. It was produced by an adjuvant created funded by the NIH. So it's better than Sinovac and sinopharm which I think the achievement is not that powerful. And the reason I want this in our future is it shows you the entire virus and I would rather have this for boosters than boosters that keep on showing you the same M. RNA vaccine, Same M. RNA spike protein. So I want the US to approve this sunday um for our booster campaigns. If we get a more virulent variant, The booster third dose absolutely did benefit people. But it really benefited those over 65, the most over 50. The next BE 18-29 year olds in Israel had no benefit from the third shot. In fact, there were zero deaths if you had two shots in 18-29 and zero deaths if you had three shots. So um certainly that age stratified analysis did not show benefit for a third shot in the 18-29 year olds. Um but it certainly benefited our older populations and those who are vaccinated were much more less likely to get sick and hospitalized during the american surge in the United States as you can see by this wide divergence. Um those who are at risk for severe breakthroughs. This is the nicest analysis I could see from the CDC from two doses are those who are over 75 and had comorbidities or those who are immunocompromised. That's why these populations were prioritized for boosting in most countries. And the fourth dose is likely the most important populations to give the fourth doses to our older people and those who are immunocompromised. Um I'm actually uh one thing I really just want to mention because I think it's really relevant for Children, but I'll actually mention it at the end. Um So okay, so what about the child vaccine? Well, As you know, the 12-18 year old vaccine has only been approved for um sorry I should say. Okay, I should say more. Clearly, the 12 to 16 year old vaccine is the 30 is the 30 microgram dose in Pfizer's. So that is the same dose that is approved for adults. So 30 micrograms for adults. 30 micrograms for 12 ana four Children, 5 to 11. The dose is 10 micrograms and um it's possible that that was a little bit under shooting of a dose because there was an analysis from new york that was published on february 28th, 2022. And again this was through the omicron surge that the 5 to 11 year old vaccine after the rollout. And remember it started being rolled out around november 4th in this country that it was less effective in 5 to 11 year olds. Now to be fair you have to look at the two types of protection. Two doses does not do it for to prevent all american infections because a micron the antibodies are so distorted they don't work as well. If you look at the old strain and you use that same vaccine against something that has that many mutations across the spike protein. But protection against hospitalizations in this age group that's your T cells did say strong. And so I think the way to message to younger to parents of younger Children is yes there at less at risk for being getting severe disease. But this was really proof that those T cells, even though they didn't measure them, these t cells are being created, B cells are being created and that that those B cells and T cells should last a long time. Um One thing that I think is really important going forward is that we can't deny that hybrid immunity is probably stronger than the immunity from the M. RNA vaccines or from any vaccines. They're just study after study that a combination of vaccination plus subsequent infection gives you more durable protection. Then if you get three vaccines or alternatively if you've just been naturally infected which is another argument um to get because to get Children vaccinated even if they've been exposed there is an anti age data hub that shows that about 70% of Children in this country between the ages of zero and 7 17 have nuclear capsule antibodies. They have been exposed to covid but getting one dose at least in the vaccine after having Covid will give you hybrid immunity and I don't have time to go through all these studies but their study after study and I'll send you these slides about how strong hybrid immunity is. And we wrote a piece for clinical infectious diseases just last month. Um talking about all of these studies, there's been two since published, one from brazil um and one from Sweden showing hybrid immunities is the strongest of all. So I definitely message to my patients who have had some natural infection. Please get at least one dose. Actually there hasn't been a benefit shown at least that you need two doses. Um We are now at a point in the pandemic where the number of covid patients in U. S. Hospitals have reached a record low. We have zero in our hospital for example across the street san Francisco general um five in the hospital at UCSF um record low since the spring of 2020 it's likely that is so much immunity from omicron and higher rates vaccination. We have at least 83% of americans have gotten one dose. Um age five and up. Which is better. Lots more vaccinations occur through surges and so I will just speak as the last part. So I can get questions on end emissivity. What does end emissivity mean? You know, I think it's um I think it's very fair to say we can't eradicate Covid and I know this is really hard for people to hear. But anyone in infectious diseases knows that there's only one virus that's ever been eradicated, working hard on polio, but we've lost some polio vaccinations. So now we're doing ring vaccination campaigns in different places including Israel. But um but only smallpox has been eradicated and there's a cattle backs, cattle virus named rinderpest that's been eradicated but they shot all the cattle. So what is the, what is the way why was smallpox eradicated? Because of four reasons that Covid doesn't have number one, no animal reservoirs. Covid has at least 29 species of animals that um carry Covid. I remember when the big cats got identified as having Covid, I thought it will never be eradicated. And now, even though there's been a lot of culling of animals in different places, Hong kong with hamsters and china right now with different animals and and Denmark killed many mink, you can't kill all animals. I mean it's really having animal reservoirs. Is it makes it impossible to eradicate Covid? The second is that smallpox look like smallpox Covid looks like a lot of different things respiratory other respiratory viruses. Smallpox has a short infectious period and Covid has a long infectious period. And finally our vaccines are great. They do protect against severe disease. But they're non sterilizing increasingly with the different variants were getting. And with our antibodies that naturally go down in the nose, we cannot, we could try but we can't really boost everyone every four months to get their antibodies up. Um, and because of that, they are non sterilizing, which was not true of smallpox. So we were able to eradicate smallpox. Um, it's not extinct by the way. It's in a certain number of labs. Um, but because that's what extinction means. Um, but we can't eradicate Covid. And so that means really a focus on severe disease and and getting some treatments because the way to keep something under control is vaccines are great. They're totally working. But we need some treatment for Covid for those who do not respond well to vaccines or for those who decline vaccination. And that's how we control pertussis. Of course new inmates as you very well know, are very are susceptible to um, pertussis. That's why we boost mothers. But but there are at least as if there are macro lights that can treat pertussis. So we need medications to treat covid, especially with vaccine hesitancy and with the vaccines not being perfect among the immuno compromised. And now we have to medical treatments beyond monoclonal antibodies that I think are huge and that they work and more are coming and they are more cooperative here which is a nucleoside analog Which prevented hospitalizations and deaths by 30%. That didn't seem great. But actually we're starting to see some real world data that it looks like it works better than that and then packs loaded actually prevented hospitalizations and deaths by 89%. Among those were unvaccinated at high risk for severe disease. Now fighter is studying packs loaded down to 12 but to be fair it is not approved for Children. Now. I think what I think is really going to happen in the world is that all of these efforts to create antivirals for covid are going to improve our treatments for some of the diseases that so in fact younger Children RNA viral antivirals were not worked on hard enough. And now I think there's going to be antivirals for RNA viruses like RSV that hopefully will protect Children from RSV. And there's a new generation um, protease inhibitor coming out that I think sprite promising for both RSV and for covid 19 and it doesn't involve Britain over here. Um, so what does the endemic stage look like? This is not where the US is this is what the U. K. Has decided the UK has, you know what endemics face looks like in the UK. It looks like normal life. There are no mask mandates no vaccine house parts. They don't even tell you to isolate for five days if you have covid no asymptomatic testing only test if you're symptomatic normal school ventilation is people want to wear masks are told the masks but they're not made to mask and wastewater surveillance. That's what it looks like in the UK. This country is Kind of in the throes of deciding right now. The CDC did change the recommendations for indoor masking to be based on hospitalizations. On February 24. So at this point actually only .53% of our counties are in a place where they need to mask indoors by the CDC criterion. Um and so as you know, uh February 16 is when not 15,000 mask mandates related in California and a month later they were lifted for Children. The president's plan to stay in the endemic fees of management as of March two, is to decide on who needs boosters who, I really think it needs to be, older people who needs prophylaxis. If they're immuno compromised with monoclonal antibodies, who needs treatment and were doing surveillance by wastewater and vaccinating the world. And those are the four White House plans for the next stage of endemic management in the United States. Same with the W. H. O. They put this out a week ago today. Um It says that we have to exit the emergency phase of the pandemic china is the only country that is still trying covid zero policies and actually there already considering changing but they're they haven't changed yet and what the W. H. O. Said based scenario where we are right now decide who needs boosters. Give them boosters when they're vulnerable. Best case we get a less virulent variant emerges. We all get immunity. We don't need boosters. The worst case more virulent variant emerges. Then we all need boosters and we likely can boost what we with what we already have. But again I have my eye on call vaccine because it shows you the whole virus. Um and we've already talked about Children and then I wanted just for the final thing where we for vaccines for um six months to six year olds. Okay you all know this? But Pfizer's three microgram dose was really small and in fact it only raised an adequate immune response by antibodies. They didn't measure t cells between six months and two years. So the FDA did not approve it because the 2 to 4 year olds didn't get a high enough antibody response. However the moderna study which just got completed did raise an adequate immune response because it was a higher dose. It was a 25 microgram dose. The usual for adults is 100. Um It raised an adequate immune response by antibodies from six months to just under six years. Now admittedly this was performed during omicron so the vaccine effectiveness was not amazing. It was 37-44% depending on what age group you're in. On the other hand there was no severe disease in the vaccine group. To be fair though there was no severe disease in the placebo group either. But um that's where we stand with the vaccine and I do think that this will be approved for six months to six year olds. And um and and and remember it's a 25 microgram dose and then I want to and then for pregnancy. Really nice studies that show that pregnancy if you're if you if the mother has antibodies from her vaccination that those antibodies go out to the newborn up to six months. So we have a way to protect everyone if the Moderna vaccine is approved. Um I do think as my final statement, I do think that the vaccine needs to be given every eight weeks apart for kids and probably up till the age of 40 and maybe even for everyone except for the immuno compromised because that both increases T cell immunity. It increases antibodies and at least if you compare Israel and Canada because Canada only did eight weeks, it did actually decrease the rare causes of myocarditis. So um I we wrote a piece for med page Now the CDC has approved this but they're not advertising a lot but they are saying eight weeks for doses for younger people