 Welcome to the Stop COVID-Dets webinar series brought to you by the University of the Philippines. The Stop COVID-Dets shorts make it easier for you to go to the presentations that you are interested in. I'm Dr. Raymond Sarmiento, director of the National Telehealth Center. And I'm Dr. Susy Pineda Mercado, adjunct faculty of the National Telehealth Center. Together, let's stop COVID-Dets. So the topic assigned to me is COVID-19 vaccines in children and I would like to thank everyone here for inviting me to give this talk. Sorry. Okay. So for my disclosure, in relation to this topic, which is on COVID-19 vaccines, I'm a member of the VEP and NAFIC. And so I will be mentioning the names of these vaccines, but I am not personally endorsing any of these vaccines. So for this afternoon, we will be discussing considerations for the use of the COVID-19 vaccines in children. What is the evidence for the safety and efficacy of these vaccines? And what are the current recommendations for the use of these vaccines in children and adolescents? Okay. So let's start. So we do know that children comprise just a small proportion of the diagnosed COVID-19 cases. They say 2% to 3% to less than 10%. However, because we do not do systematic testing of cases, of pediatric cases for COVID and because most of these children may present with mild disease or are actually asymptomatic, we don't actually know the true burden of pediatric COVID infections. So as we already mentioned, COVID-19 disease in children is generally mild with an overall good prognosis compared to adults. However, the presence of underlying medical conditions or certain co-infections may actually increase the risk for severe or critical disease in children. So the classification of COVID-19 disease in children is based on severity and 80% would present with mild to moderate COVID. 2% to 12% would be severe and about 2% to 10% critical. So 80% moderate to mild and only about 20% would be severe or critical. So what are these risk factors that increase the severity of COVID-19 in children? So the presence of cardiovascular disease, neurologic conditions, neurodevelopmental disorders, chronic lung disease, immunosuppression, cancer or malignancies, genetic endocrine diseases, as well as obesity and prematurity would increase the risk for severe COVID in children. And we also have what we know as this hyper inflammatory syndrome in children, the multi-system inflammatory syndrome in children, which resembles Kawasaki disease and is actually considered as severe COVID. So this disease might occur during, so with the COVID infection or may present after COVID infection. So what are the considerations for use of the COVID-19 vaccines in children and adolescents knowing that background? So we have a certain considerations starting with the epidemiology or burden, the safety and efficacy or effectiveness of the vaccine. So mathematical modeling relating to population level impact of vaccinating this age group. What are the programmatic implications, potential vaccination delivery challenges and acceptance of the vaccination in this age group? So we heard what the person on the street or what the parents were actually saying about accepting this COVID-19 vaccines for their own children. So let's start with the epidemiology or disease burden of COVID-19. So in countries where the proportion of young in the population is high, over one-third of COVID-19 cases occur in children. And most of the cases are mild as we already said, but still a significant number, about 20% will present with severe or even critical disease that will require ICU admission or even result in mortality. And there are some children who experience long COVID symptoms. Increased transmissibility of the Delta variant across all age groups results in maybe that's the reason why we are seeing an increasing number of cases in children. And the emergence of new variants may also pose a greater risk if the children and adolescents remain susceptible or non-immune. And with older age, the older age groups being increasingly protected by vaccination, a greater proportion of COVID-19 is now anticipated to occur in the younger age groups, so the adolescents and children. And the growing number of these unvaccinated children with increase in the numbers added to the birth cohort with the deliveries. This will result in ongoing transmission. So this is the latest data that I was able to get as of September 29, I'm sure meron ng September 30, but there were 2.5 million cases of COVID-19. And of these positive cases, about 10% would be less than 20 years old and of that around 6% would be less than 15. So we see that there are children who are being infected. And if we take a look at the population pyramid of the Philippines, which is very similar to what we would expect in developing countries, we have a young population. So more of our people, our population would be in the younger age groups. So for example, in this 2020 population pyramid, about 30% would be less than 14, and about 20% would be 15 to 24 years old. So this is in contrast, for example, to industrialized countries where you expect more of the population to be older and even elderly population. So we are a young population. And this is important to consider when we talk about herd immunity. So herd immunity can only be achieved if we have a significant proportion of the population who are immune either through vaccination or from getting the infection. And of course, we want to make sure that we achieve herd immunity by increasing vaccination coverage, not by increasing the exposure of our people because that would result in unnecessary cases and even deaths. So what we want to do is to increase the vaccination coverage in order to reach herd immunity. Now the threshold to be able to reach that herd immunity is based on a number of factors, including the contagiousness of the virus, which is given here as the basic reproduction number or the R naught, as well as the efficacy or effectiveness of the vaccine. So for COVID, for example, for SARS-CoV-2, the herd immunity threshold is placed at 60% to 80%. Now, as I mentioned, it will depend of course on the efficacy of the vaccine. For example, on the graph on the left, if you have a vaccine efficacy of about 90 to 95% with an R naught or contagiousness of 2.5, which means that for every infected individual, he or she will now spread it to 2.5 more people. With that, you will need a vaccination coverage of around 70% to 80%. But with lower vaccine efficacy, for example, if the vaccine efficacy is only 62%, then take note, you will need to vaccinate almost all of the population. And this includes children. So when you say that you will vaccinate 80% to 90% of the population, that does not mean 80% to 90% of those who are 60 years old and above or 80% to 90% of the frontliners. No, it means 80% to 90% of the entire population and that will of course include children. So this just shows you how important third immunity is. And if I may borrow a saying, it mentions that no one is safe unless everyone is safe and that of course includes your children and adolescents. So let's move on to the next consideration for introducing vaccines in children. And this should be based on vaccine safety, efficacy and effectiveness that we derive from clinical trials as well as effectiveness data from real world vaccination program experiences. And what we know is that there is actually high level evidence with regards to safety, strong immunogenicity and efficacy of the COVID-19 vaccines for adolescents for the two mRNA vaccines. So in this first study, this is a phase three trial to determine the safety, immunogenicity and efficacy of the Pfizer, which is now called the Comir Nati vaccine in adolescents 12 to 15 compared to young adults 16 to 25 years. So in this trial, they enrolled or included more than 2200 adolescents aged 12 to 15 to receive two doses of the Pfizer vaccine given 21 days apart. And the data would show that it has a favorable safety and side effect profile. If you take a look at the right side on the bar graphs here, we show that most of the side effects are mild as seen here by the green bars or moderate as seen here by the blue bars. So for the local side effects, the most common would be injection side pain. And for the systemic side effects, the most common would be fatigue, headache and chills. So these are not uncommon reactions seen with other vaccines. So they are not unusual. And severe reactions occurred, but in fact, they were even lower in the younger age group compared to the young adults. And fortunately in this trial, there were no vaccine related serious adverse events and only a few overall severe adverse events seen. Now what about the antibody titers? So if we take a look at the geometric mean neutralizing antibody titers for the 12 to 15 year age group, it was 1239. And this is 1.8 times higher than the 16 to 25 years age group. So it means that it is immunogenic. The vaccine is immunogenic in the 12 to 15 year old age group. And in fact, it even gives rise to higher neutralizing antibodies compared to the young adults 16 to 25 years. For vaccine efficacy in preventing COVID-19, symptomatic COVID-19 after two doses in participants without evidence of previous infection. And even in those who were previously infected, the efficacy is 100%. So with a range of around 75 to 100%. So it's a very good efficacy. Now this second study is a phase two, three clinical trial evaluating the Moderna vaccine in adolescents 12 to 17 years compared to the young adults 18 to 25 years. So Moderna or the Moderna vaccine is also given as two doses 28 days apart. And what was shown is that the side effects or the adverse events that were seen were also not unusual. So the most common solicited adverse reactions after both the first and second injections were injection site pain, headache and fatigue. So similar to the Pfizer vaccine. Most of the reactions were seen after the second dose and most were mild or grade one. Again, represented by the green bars or moderate represented by the blue bars. So there were no serious adverse events related to the study vaccines. There were a few severe reactions, local and systemic reactions represented by the orange bars, but they were very few. Now with regards to immunogenicity, the geometric mean titers in the 12 to 17 year age group compared to the 18 to 25 year age group is not really significantly different, but not inferior. So it is not inferior and it is similar. The titers in the younger age group 12 to 17 is not inferior to the antibody titers seen in the 18 to 25 year age group. And for vaccine efficacy against COVID-19, there were no cases of COVID-19 seen in those who were given the Moderna vaccine, but there were four cases of COVID-19 given seen in the placebo group, which gives vaccine efficacy of 100%. Now using a different definition, a more, what do you say, a more not stricter, what's the opposite? Easier definition, just respiratory symptoms, any respiratory symptom with a positive test. Then the vaccine efficacy is still high, it's still 93%. So again, very good. Now let's talk about vaccine effectiveness. There are really no published effectiveness studies of the COVID-19 vaccine in adolescents or children. And vaccine effectiveness can however be inferred from the immunogenicity data that we have. So this is called immunobridging analysis. So the effectiveness is inferred from the neutralizing antibodies that is considered to be clinically relevant to infer effectiveness in the pediatric age group. And of course we do not have yet a specific antibody titer to establish or predict protection. But what we want to show is that it is not inferior or better if it is similar or even greater compared to the young adults. And that is what we have demonstrated in the two of the important studies regarding the mRNA vaccines. So we consider both the geometric mean titers and the zero response. And we compare the response that we see in adolescents versus the young adult populations. And again, as we mentioned, similar or not inferior. Now there is actually one vaccine effectiveness study in children and adolescents. But this is not published yet. This is just presented in this editorial. And what I am presenting now is the interim analysis. So this study was conducted in Israel. As we know Israel is one of the countries with the most rapid and effective successful vaccine rollout. So they started during the last quarter of last year. And then in January of this year, they already included the 16 to 18 years, a 16 to 18 year old in the priority vaccination group. So they were able to vaccinate more than 200,000 at the time that they did the analysis. And it showed a vaccine effectiveness against symptomatic COVID-19 of 98% and a similar effectiveness against hospitalization in the 16 to 18 year old age group. And there were no cases of severe or critical COVID-19. And in those who were vaccinated, whereas in the unvaccinated group, 15 were hospitalized to in critical condition and one died. So they had very good experience in Israel. So to maybe summarize what we have seen, the data we have seen in the two studies as well as the vaccine effectiveness study in Israel, the mRNA vaccine, so both the Pfizer and Moderna vaccines produced a greater or similar immune response compared to young adults. Both had a favorable safety profile and both were highly effective against COVID-19. So let's talk a little bit more about adverse events and side effects because as we heard from many people, this is actually a concern. So as we saw from the clinical trials and even from the real world experience in Israel, there were no unusual side effects. Most of the side effects were local or systemic adverse effects and these were mild to moderate. Allergic reactions, mild allergic reactions were seen, but anaphylaxis was rare. And rarer still is the immune-mediated adverse event of immune thrombocytopenia seen in less than one in a million. But what was truly concerning were the reports of myocarditis or pericarditis or myopericarditis in 12.6 per one million vaccinated individual, vaccinees. So this was a bit concerning because it is greater or higher than the expected rates. So in the United States, they have two vaccine safety surveillance systems. The first is the Vaccine Adverse Events Report System or the VAERS. And the other is the V-Save Health Check-In Survey which is a smartphone-based safety surveillance reporting system. So here, the adolescents who were vaccinated can register and actually directly report whatever side effects they are experiencing. And we see here that again, no unusual adverse effects, local and systemic reactions were reported, especially after those two, but nothing unusual. This is what we usually see with the other vaccines. Now, there were also a few who actually needed medical care or were hospitalized, very few, but because it is a passive type of reporting, we don't really know what was the cost for the vaccination. So in terms of the V-Save Health Check-In Survey, involving 129,000 adolescents aged 12 to 17, no safety alarms. However, for the Vaccine Adverse Event Reporting System or the VAERS from December to July 16, so although 90% would be non-serious, 10% reported serious adverse events. And here, you will notice that myocarditis was actually reported in 40% of the serious or 397 out of a total of 9,246 reports, so that's about 4.3% reported myocarditis. And you will also note that many of the side effects reported were actually related to myocarditis such as chest pain, increased troponin, normal echocardiogram. So these may be related to the myocarditis. So how was the myocarditis diagnosed in patients who received the vaccine? So by echocardiography, what they usually would see would be a reduced or diminished ventricular function or abnormal ejection fraction. And some of the cases would present with mild blural effusion. These figures, these pictures actually show results from the cardiac MRI, cardiac resonance imaging after receiving the vaccine. And what is demonstrated here is enhancement of the subepicardial and mid-myocardial sections, particularly the inferior and inferior ventricular walls. So this is what you would demonstrate when you do a cardiac MR for patients with myocarditis. So what do we know about myocarditis or pericarditis after the mRNA vaccines? So we do know that myocardial injury has been reported in 36% of hospitalized COVID-19 patients. So it's actually part of COVID-19 infection and it can occur even after the patients have recovered from COVID-19. And 36% is higher than what we see in patients, in normal people who received the vaccine. So myocarditis or myocardial injury occurs in a higher percentage of those who are infected compared to those who are vaccinated. So the overall incidence of myocarditis per one million doses administered is 12.6% for both mRNA vaccines combined. The incidence is greater in male, adolescents and young adults 12 to 29 years, so less than 30 years old. Usually seen in the first seven days or within three weeks after the second dose. So the risk is greater in males and after the second dose. How do they present? They present with chest pain, shortness of breath or palpitations. And how they are diagnosed either by elevated troponin levels or abnormal findings on the ECG, echocardiogram or cardiac MRI such as what I showed you earlier. But the good thing is in those cases of myocarditis that develop after vaccination, 95% of the cases were mild and recovered on their own. It was transient lasting only for about two to three days and were just given minimal treatment with for example, incense and rest. So they were very mild and transient. Now the CDC, before they recommended to include vaccinating children, conducted this risk benefit analysis to compare the benefit of giving the vaccine in terms of preventing COVID-19 cases, hospitalization, ICU admissions and even deaths and compare this with the risk of myocarditis. And what we see here is that across the ages, the benefits actually outweigh the risk. However, the benefit and the risk is not balanced across the ages. Why? Because we see poorer outcomes of the COVID-19 disease in those who were greater than 30 years old and a greater risk of myocarditis in those who are younger. So if, for example, we take the age group 12 to 17 because that is our focus for this morning and per 2 million mRNA vaccine doses administered among the males, we see that there will be 5700 cases prevented, 215 hospitalizations prevented, 71 ICU admissions and two deaths prevented. However, there will be 56 to 69 cases of myocarditis that can be reported. So with this particular data, the CDC ACIP advisory group with regards to vaccination concluded that for COVID-19 vaccines, the benefits will still outweigh the risk even for the younger age group, including adolescents. And the risk meaning including myocarditis. And it is important to monitor the outcome of the myocarditis in those who develop this after vaccination. So there is continued monitoring of these cases because we do not know what the long-term effect will be. And thirdly, they would like this information to be disseminated so that people will be aware of what to watch out for after vaccinating. But I guess the bottom line is the myocarditis and pericarditis are much more common if you get the disease rather than from the vaccine. And the risk to the heart from the infection can be more severe, okay? And there is another risk-benefit assessment this time conducted by UK by the Joint Commission on Vaccination and Immunization. Again, they did this because they also were studying whether to recommend the COVID-19 vaccines for adolescents. And here they showed that the benefit of the vaccine for the first dose, it will prevent two intensive care admissions and 87 hospital admissions, but may result in three to 17 cases of myocarditis. And they saw that this was more acceptable, the first dose. But for the second dose, they are a little bit wary because it would prevent 0.16 ICU admissions, six hospitalizations, but will result in a higher number of cases of myocarditis. I guess this is the reason why in their recommendation, they would rather focus on giving the first dose first to all the adolescents before they give the second dose. So what are the benefits of COVID-19 vaccination? It will prevent COVID-19 and its complications. It will reduce transmission in the broader population and in this specific setting, which is children adolescents in the schools, it will prevent transmission. It will mitigate the psychosocial impact resulting from disruption in school, sports, other organized activities, socializing because of the isolation of this age group. That are key to adolescent physical and mental well-being, and I think that is very important also to consider. So what are the recommendations? I'm into my last few slides. AAP, as of August 2, 2021, they recommend vaccinating all children and adolescents 12 years of age and older who do not have contraindications. What vaccines do they use? Those vaccines that have been approved by the US FDA and recommended by the CDC. And lastly, because of the importance of routine vaccination and rapid uptake of COVID-19 vaccines, then they support co-administration with the other routine and adolescent immunizations. So CDC recommends vaccination for everyone age 12 years and older to prevent the corona disease 2019. So adolescents age 12 to 17 are eligible to receive the Pfizer vaccine and they may be vaccinated with appropriate consent and assent. Children younger than 12 years are not eligible to receive Pfizer vaccine at this time. And children and adolescents younger than 18 are not eligible to receive the Moderna or Janssen COVID-19 vaccine at this time. So only Pfizer is recommended or approved for children less than 18, 12 to 17 years old. So what are the countries with an EUA for this vaccine, for the Pfizer vaccine? You have quite a number and some of them have actually already started vaccinating the adolescents. Initially, some of them would start with those with underlying medical conditions but would later on move to universal or routine vaccination of all children 12 to 17 years old. We see here that in the Philippines, we already actually have an EUA for Pfizer in May 2021 and for Moderna, an FDA EUA in September 2021. So for both for active immunization for the prevention of COVID-19 in individuals 12 years of age and older. So they had an amendment of their EUA because previously only for 18 and above. So what does the National COVID-19 Vaccination Operations Center have to say about this? So I think there is no argument that these vaccines, the mRNA vaccines are effective and safe for children. The Department of Health, all expert group, reiterates their initial recommendation that vaccination of children and adolescents, even those with comorbidities, shall only begin once the supply of vaccines is adequate and stable. So I think there is no issue about the efficacy, safety, it's more on supply. And this is reiterated by the PPS and PIDSP who recommend that the priority should still be the older and more vulnerable adult age group. And once we have a sufficient percentage of these priority adult groups that have been vaccinated, then we can start vaccinating children 12 years old and above. And priority is given to those in areas with high transmission and those with comorbidities. And the fear then was that if you give pediatric vaccination at a time when we still did not have sufficient numbers of our adult priority adult groups vaccinated or insufficient vaccine supply, then this may disenfranchise the limited supply of vaccines to the more vulnerable groups such as the senior citizens and adults with comorbidities. So in view of that, as of August 11, we were not yet vaccinating children 17 years old and below. However, two days ago, three days ago, President Duterte already announced that immunocompromised children 12 to 17 will be vaccinated and this vaccination will start in October. So the Department of Health announced that adolescents with comorbidities will be added to the A3 priority sector and they will be given Pfizer and Moderna or Moderna COVID-19 vaccines. So the government is aiming to start October 15 because the capital region in Manila already has an impressive vaccination coverage. And I think we have been assured that by October, we will have enough supplies. And then after Manila, then they could expand to other regions after the first two weeks of the pilot implementation. Now there are other vaccines, COVID-19 vaccines that have been, that are being studied. So Novavax, Janssen, AstraZeneca and the Pfizer and Moderna have ongoing studies in funds as young as six months. Sinovac also has actually a study on children 3 to 17 years old. They have actually published a paper, which is a phase one, two clinical trial and which concluded because this is the first report of an inactivated vaccine, the CoronaVac, being tested in children and adolescents 3 to 17 years old. And because it is just a phase one, two clinical trial, which is mostly safety and immunogenicity, they found that it was relatively safe and immunogenic in this age group. So we look forward to their later phase three trials that can be published soon. So the ongoing challenges in the COVID-19 vaccination of children and adolescents is again because of the constraints on vaccine supply. So that is a key determinant. And when we start vaccinating children and adolescents, we have to augment the existing infrastructure for vaccination. So we need to make sure that there are care providers that are experienced in dealing with children and adolescents who are being vaccinated. And of course, logistical concerns because we know that the Pfizer vaccine needs ultra low freezer storage requirements. So that might be an issue. And data on vaccine safety is ongoing. We are still following up these children who develop adverse events and we are continuously monitoring the long term effects of the vaccine in children and adolescents. So in summary, children and adolescents represent a growing proportion of new COVID-19 cases. Children and adolescents can experience serious outcomes from infection and can transmit the virus. COVID-19 mRNA vaccines have been shown to be safe, effective, immunogenic in preventing COVID-19, and vaccinating children against COVID-19 will be essential to protect their health and to establish higher population immunity. So that's the end of my slide. Thank you very much for listening. We hope that you learned as much as we did from that excellent presentation. 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