Virus World

BACKGROUND

Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.

METHODS

Part 1 of this ongoing phase 2–3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.

RESULTS

In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.

CONCLUSIONS

Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896. opens in new tab.)

Published in NEJM (May 11, 2022):

https://doi.org/10.1056/NEJMoa2203315 

An FDA advisory panel voted in favor of authorizing the Pfizer/BioNTech Covid-19 vaccine for children between the ages of 5 and 11. After sometimes tense deliberations that weighed the benefits of vaccination against potential risks, the Vaccines and Related Biological Products Advisory Committee voted 17-to-0 with one abstention on Tuesday that two 10-microgram doses of the vaccine should be granted emergency use authorization, a clearance that will remain in effect only as long as the pandemic is considered a public health emergency.  The FDA is not bound by the votes of its advisory committees, which it convenes to ask for guidance, but it generally follows their advice. Before the vaccine becomes available, it will also need to be reviewed by another committee, the Advisory Committee on Immunization Practices, which is convened by the Centers for Disease Control and Prevention, and the CDC director will need to affirm the ACIP’s decision. Pfizer and BioNTech presented data from a study of 1,518 children who received the 10-microgram vaccine — one-third the adult dose — and another 750 who received placebo. The vaccinated volunteers were 90.7% less likely to develop symptomatic Covid, and when they did become ill, their symptoms were less severe.

The panel weighed the benefits of preventing Covid-19 against the risks of the vaccine, in particular the risk of the heart conditions myocarditis and pericarditis, which, though hard to measure exactly, appear to occur once per every 10,000 or so boys and young men vaccinated. The cases seen after use of the vaccine appear to be milder than regular cases of the inflammatory condition, and last for a shorter time. The panel agreed with the FDA’s own scientists that the risk of Covid during the pandemic far outstripped the risk of myocarditis, even if transmission of the virus is relatively low in a given area. More than that, panelists felt that there were some children who definitely needed access to the vaccine. Many said that they were leaving it to the CDC’s ACIP committee to make recommendations regarding which children should receive the vaccine.  In an analysis released before the meeting, FDA analysts used mathematical modeling to estimate how many hospitalizations would be prevented if a million boys ages 5 to 11 were vaccinated at six different points in the pandemic in the United States. At most points, the vaccine would prevent 200 to 250 hospitalizations per every million boys vaccinated. At points when transmission of the virus was low, the vaccine would only have prevented only 21 hospitalizations per 1 million boys. The analysts said that while that suggests the vaccine might trigger slightly more myocarditis-related hospitalizations in boys than Covid-19 hospitalizations it would prevent in the same population, the benefits still might outweigh the risks, given that Covid cases that require hospitalization are generally more severe than myocarditis cases. The FDA also said that its estimate of myocarditis risk was “conservative,” meaning that the risk for children in the 5 to 11 age group might be lower.

Vaccinated kids aged 5 to 11 showed evidence of protection against the virus, the company said. The data must be reviewed by the F.D.A. before children can be inoculated.  The Pfizer-BioNTech coronavirus vaccine has been shown to be safe and highly effective in young children aged 5 to 11 years, the companies announced early Monday morning. The news sets the stage for authorization of the vaccine for younger children, possibly before the end of October. The need is urgent: Children now account for more than one in five new cases, and the highly contagious Delta variant has sent more children into hospitals and intensive care units in the past few weeks than at any other time in the pandemic. Pfizer and BioNTech plan to apply to the Food and Drug Administration by the end of September for authorization to use the vaccine in these children. If the regulatory review goes as smoothly as it did for older children and adults — it took roughly a month — millions of elementary school students could begin to receive shots around Halloween. Trial results for children younger than 5 are not expected till the fourth quarter of this year at the earliest, according to Dr. Bill Gruber, a senior vice president at Pfizer and a pediatrician. Results from Moderna’s vaccine trials in children under 12 are also expected around that time, said Dr. Paul Burton, the company’s chief medical officer.  Pfizer and BioNTech announced the results in a statement that did not include detailed data from the trial. The findings have not yet been peer-reviewed nor published in a scientific journal. But the new results dovetail with those seen in older children and in adults, experts said. “There’s going to be a huge number of parents who are going to heave a big sigh of relief when they hear this,” said Dr. Kristin Oliver, a pediatrician and vaccine expert at Mount Sinai Hospital in New York. “We’ve been waiting for these kids to be protected.”

Before the vaccine can be authorized, F.D.A. scientists must carefully sift through the data, looking for side effects the company may have missed, which may slightly delay the process.

Children have a much lower risk of Covid-19 than adults, even when exposed to the Delta variant. Still, some small number of infected children develop a life-threatening condition called multi-system inflammatory syndrome in children, or MIS-C. Still others may have lingering symptoms for months. Nearly 30,000 children were hospitalized for Covid in August; the least vaccinated states reported the highest rates. At Seattle Children’s hospital, about half of the children who are admitted for Covid are older than 12, according to Dr. Danielle Zerr, a pediatric infectious diseases expert at the hospital. “I’ve been dismayed at the fact that the sickest children in our hospital with acute Covid-19 or MIS-C are children who could have been vaccinated,” Dr. Zerr said.  As ideological battles over masking and vaccine mandates play out in communities, the reopening of schools has fueled the surge. In Mississippi, among the states without a mask mandate, nearly 6,000 students tested positive for the virus in one week, and more than 30,000 students, teachers and staff had to be quarantined. One county in South Carolina — where mask mandates are banned — had to quarantine more than 2,000 students in one day. Remote learning is not an option in many districts, so the safety of some medically vulnerable children in many parts of the country has become subject to the actions of others. The trial results were greeted enthusiastically by many school administrators and teachers’ organizations, but are unlikely to lead to immediate policy changes. “This is one huge step toward beating Covid and returning to normalcy. I don’t think it changes the conversation around vaccine requirements for kids,” said Randi Weingarten, president of the American Federation of Teachers, a national union. Ms. Weingarten noted that parents and educators were still awaiting full F.D.A. approval of vaccines for children aged 12 to 15, and that mandates for adults did not come until months after the shots first became available....

Pfizer release (Sept. 20, 2021) available at:

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-positive-topline-results 

The first children have been vaccinated in Moderna's Phase 2/3 pediatric Covid-19 vaccine trial, the company announced Tuesday in a statement. The clinical trial, called the KidCOVE study, will enroll approximately 6,750 children in the US and Canada between the ages of 6 months and 11 years old.  The trial is broken into two parts. In part one, different dosages of the vaccine are being tested on the children. Children between the ages of 6 months and 1 year old will receive two doses of the vaccine spaced about 28 days apart at either a 25 or a 50 or a 100 microgram level. Children between the ages of 2 and 11 will receive two doses of the vaccine spaced about 28 days apart at either a 50 or a 100 microgram level. The findings of part one will be used to determine which dose will be used in part two. For part two, the trial will expand to include children who are given a saline placebo, which does nothing. The children will be followed for 12 months after their second injection.

Fully vaccinating children reduced the risk of hospitalization for complications associated with influenza by 54%, according to a new study by Ben-Gurion University of the Negev (BGU) and University of Michigan researchers. The research, published in the December, 2019 print journal Clinical Infectious Disease, is one of the few studies worldwide that has tested the effectiveness of childhood vaccination against influenza and risk of hospitalization due to the influenza complications. The study was led by Dr. Hannah Segaloff, an epidemiologist at the School of Public Health, University of Michigan and Prof. Mark Katz, M.D., of BGU's Department of Health Management, Faculty of Health Sciences and a senior researcher at the Clalit Institute of General Research. Prof. Katz also teaches in BGU's Medical School for International Health.

The retrospective study reviewed the vaccination data of 3,746 hospitalizations of children ages six months to 8 years old at six hospitals in Israel. They were tested for influenza over three winter seasons 2015-16, 2016-17 and 2017-18. The findings reveal that the flu vaccine reduced hospitalizations associated with the flu by more than half. They also validate guidelines in the United States and Israel that recommend two vaccine doses for children up to age 8 who have never been vaccinated or who previously received one dose. "Children vaccinated according to government guidelines are much better protected from influenza than those who only receive one vaccine," says Dr. Segaloff. "Over half of our study population had underlying conditions that may put them at high risk for severe influenza-related complications, so preventing influenza in this group is critically important.

Published in Clinical Infectious Diseases:

https://doi.org/10.1093/cid/ciz125

While protection against hospitalization is still strong, the vaccine offered almost no protection against infection, even just a month after full vaccination.  The coronavirus vaccine made by Pfizer-BioNTech is much less effective in preventing infection in children ages 5 to 11 years than in older adolescents or adults, according to a large new set of data collected by health officials in New York State — a finding that has deep ramifications for these children and their parents. The Pfizer vaccine is the only Covid shot authorized for that age group in the United States. It still prevents severe illness in the children, but offers virtually no protection against infection, even within a month after full immunization, the data, which were collected during the Omicron surge, suggest. The sharp drop in the vaccine’s performance in young children may stem from the fact that they receive one-third the dose given to older children and adults, researchers and federal officials who have reviewed the data said. The findings, which were posted online on Monday, come on the heels of clinical trial results indicating that the vaccine fared poorly in children aged 2 to 4 years, who received an even smaller dose.

Experts worried that the news would further dissuade hesitant parents from immunizing their children. Other studies have shown the vaccine was not powerfully protective against infection with the Omicron variant in adults, either. “It’s disappointing, but not entirely surprising, given this is a vaccine developed in response to an earlier variant,” said Eli Rosenberg, deputy director for science at the New York State Department of Health, who led the study. “It looks very distressing to see this rapid decline, but it’s again all against Omicron.”  Still, he and other public health experts said they recommend the shot for children given the protection against severe disease shown even in the new data set. “We need to make sure we emphasize the doughnut and not the hole,” said Dr. Kathryn M. Edwards, a pediatric vaccine expert at Vanderbilt University. In their study, Dr. Rosenberg and his colleagues analyzed data from 852,384 newly fully vaccinated children aged 12 to 17 years and 365,502 children aged 5 to 11 years between Dec. 13, 2021, and Jan. 31, 2022, the height of the Omicron surge.

The vaccine’s effectiveness against hospitalization declined to 73 percent from 85 percent in the older children. In the younger children, effectiveness dropped to 48 percent from 100 percent. But because few children were hospitalized, these estimates have wide margins of error. The numbers for protection from infection are more reliable. Vaccine effectiveness against infection in the older children decreased to 51 percent from 66 percent. But in the younger children, it dropped sharply to just 12 percent from 68 percent. The numbers change drastically between ages 11 and 12. During the week ending Jan. 30, the vaccine’s effectiveness against infection was 67 percent in 12-year-olds but just 11 percent in 11-year-old children. “The difference between the two age groups is striking,” said Florian Krammer, an immunologist at the Icahn School of Medicine at Mount Sinai. The biological difference between the two ages is likely to be minimal, but while 12-year-old children got 30 micrograms of the vaccine — the same dose given to adults — children who were 11 received only 10 micrograms, he noted. “This is super interesting because it would almost suggest that it’s the dose that makes the difference,” he added. “The question is how to fix that.” There have been at least 851 deaths involving Covid-19 in children under 17, and nearly 7,000 cases of multisystem inflammatory syndrome in children, a rare but serious condition associated with Covid. More children were hospitalized during the Omicron surge than at any other point in the pandemic. The findings underscore the need to gather more information on the best dose, number and timing for the shots given to children, Dr. Rosenberg said. They also underscore vaccines as just one measure of protection from the virus, along with masks and social distancing, he said.

Dr. Rosenberg’s research was posted just days after the Centers for Disease Control and Prevention released new recommendations that would allow the majority of Americans to stop wearing masks, including in schools. The new data also raises important questions about the Biden administration’s strategy for vaccinating children. Only about one in four children aged 5 to 11 years has received two doses of the vaccine. (The C.D.C. has not yet recommended booster doses for this age group.) The vaccine has not yet been authorized for children younger than 5. Scientific advisers to the Food and Drug Administration were scheduled to meet on Feb. 15 to evaluate two doses of the vaccine for the youngest children, while three doses were still being tested. But the meeting was postponed after Pfizer submitted additional data suggesting two doses were not strongly protective against the Omicron variant of the virus. Dr. Rosenberg briefed top C.D.C. officials, including Dr. Rochelle P. Walensky, the agency’s director, with findings in early February. F.D.A. leaders learned of the data around the same time. Some federal scientists pushed for the data to be made public ahead of the F.D.A. expert meeting scheduled for Feb. 15, viewing it as highly relevant to the discussion about dosing in children under 5, federal officials and others familiar with their responses to it said....

Cited research available as preprint (Feb. 28, 2022):

https://doi.org/10.1101/2022.02.25.22271454 

Kid-size doses of Pfizer’s COVID-19 vaccine appear safe and nearly 91% effective at preventing symptomatic infections in 5- to 11-year-olds, according to study details released Friday as the U.S. considers opening vaccinations to that age group. The shots could begin in early November, with the first children in line fully protected by Christmas, if regulators give the go-ahead. That would represent a major expansion of the nation’s vaccine drive, encompassing roughly 28 million elementary school-age youngsters. Details of Pfizer’s study were posted online. The Food and Drug Administration was expected to post its own review of the company’s safety and effectiveness data later in the day. Advisers to the FDA will publicly debate the evidence next week. If the agency itself authorizes the shots, the Centers for Disease Control and Prevention will make the final decision on who should receive them. Full-strength Pfizer shots already are authorized for anyone 12 or older, but pediatricians and many parents are anxiously awaiting protection for younger children to stem rising infections and record hospitalizations among them from the extra-contagious delta variant and to help keep kids in school. The Biden administration has purchased enough kid-size doses — in special orange-capped vials to distinguish them from adult vaccine — for the nation’s 5- to 11-year-olds. If the vaccine is cleared, millions of doses will be promptly shipped around the country, along with kid-size needles. More than 25,000 pediatricians and primary care providers already have signed up to get the shots into little arms.

The Pfizer study tracked 2,268 children in the 5-to-11 group who got two shots three weeks apart of either a placebo or the low-dose vaccine. Each dose was one-third the amount given to teens and adults. Researchers calculated the low-dose vaccine was nearly 91% effective, based on 16 COVID-19 cases in youngsters given dummy shots versus three cases among vaccinated children. There were no severe illnesses reported among any of the youngsters, but the vaccinated ones had much milder symptoms than their unvaccinated counterparts. Most of the study data was collected in the U.S. during August and September, when the delta variant had become the dominant COVID-19 strain. In addition, young children given the low-dose shots developed coronavirus-fighting antibody levels just as strong as teens and young adults who got regular-strength vaccinations. In another piece of encouraging news, the CDC reported earlier this week that even as the delta variant surged over the summer, Pfizer vaccinations were 93% effective at preventing hospitalizations among 12- to 18-year-olds. Pfizer’s study of younger children found the low-dose shots proved safe, with similar or fewer temporary side effects such as sore arms, fever or achiness that teens experience. The study isn’t large enough to detect any extremely rare side effects, such as the heart inflammation that occasionally occurs after the second dose, mostly in young men. While children run a lower risk of severe illness or death than older people, COVID-19 has killed more than 630 Americans 18 and under, according to the CDC. Nearly 6.2 million children have been infected with the coronavirus, more than 1.1 million in the last six weeks as the delta variant surged, the American Academy of Pediatrics says. Moderna also is studying its COVID-19 shots in elementary school-age youngsters. Pfizer and Moderna are studying even younger children as well, down to 6-month-olds. Results are expected later in the year.

Results of the Study available in the FDA site:

https://www.fda.gov/media/153409/download 

Vaccinating many people against SARS-CoV-2 could stall infection rates even among unvaccinated children in the same community. Last December, Israel launched one of the fastest vaccination schemes in the world, reaching 50% of the population in 9 weeks. But only people aged 16 and over were eligible for the jab.

To test the ripple effects of widespread vaccination, Tal Patalon at Maccabi Healthcare Services in Tel Aviv-Yafo, Israel, Roy Kishony at the Technion — Israel Institute of Technology in Haifa and their colleagues analysed COVID-19 vaccinations and test results recorded between January and March 2021 for people in 223 Israeli communities (O. Milman et al. Preprint at medRxiv https://doi.org/f4d7; 2021). In each community, the authors examined the relationship between the vaccination rate in adults over three 3-week intervals and the rate of positive results for a COVID-19 test in children 35 days later. The authors found that, in the weeks after older people had received the Pfizer–BioNTech vaccine, the infection risk among children under 16 dropped proportionally to the percentage of adults who had been vaccinated. The authors warn that their results might be influenced by children who had previously been infected, even though the study included communities with low infection rates. The findings have not yet been peer reviewed.

Preprint available in medRxiv (March 31, 2021):

https://doi.org/10.1101/2021.03.26.21254394 

Moderna has dosed the first adolescents in a phase 2/3 clinical trial designed to position its COVID-19 vaccine for use in children as young as 12 years old before the start of the 2021-22 school year. Having shown mRNA vaccine mRNA-1273 is safe and effective in adults, Moderna is now running a 3,000-subject trial in adolescents. Moderna is aiming to deliver data in adolescents in the spring of 2021, setting it up to get an expanded label in time for a vaccination campaign ahead of the next school year. “By the time we go back in September 2021, the kids can go back to school with a normal school year, which is so important to know in terms of equality and then kids’ development and education and mental health and so on. That's our plan for adolescents,” Moderna CEO Stéphane Bancel said at a recent investor event.  COVID-19 outcomes in adolescents are typically better than in adults, with the severity of disease roughly correlating with age. However, children have been negatively affected by school closures, particularly in the U.S. where states have been accused of prioritizing businesses over K-12 when it comes to making decisions about what to shut to control the coronavirus. Countries in Europe have typically prioritized keeping schools open. Moderna wants to help states keep schools open next year—and access an additional population—by running a clinical trial that will randomize adolescents to receive either the 100-μg vaccine dose used in the adult phase 3 or placebo. Like adults, adolescents will receive two doses 28 days apart.  

The size of the trial and rate of symptomatic COVID-19 in adolescents means Moderna is unlikely to be able to show its vaccine prevents disease by the spring. However, if a correlate of protection is found, Moderna could use that to infer efficacy. Alternatively, the biotech will infer efficacy through immunobridging to the adult population. Safety and reactogenicity are the primary endpoints.  COVID-19 vaccine trials have so far mainly enrolled adults aged 18 years and older. Pfizer amended its phase 2/3 protocol to support enrollment of younger people partway through the trial and sent the FDA reactogenicity data on 100 adolescents aged 12 to 15 years in its filing for emergency use authorization. However, Pfizer is not currently seeking EUA in children as young as 12 years as it has too few data to support a favorable benefit-risk determination.  Pfizer is seeking authorization in adolescents aged 16 and 17 years, though, despite lacking solicited reactogenicity data as of the cutoff for the EUA. Reactions were detected and reported as unsolicited adverse events. The EUA safety population includes data on 283 people aged 16 or 17 years. Having administered its vaccine to hundreds of adolescents, Pfizer is ahead of Moderna in the race for that part of the market. But the potential for the back-to-school period to see surging demand for vaccines authorized for use in adolescents suggests Pfizer’s lead may not translate into a meaningful advantage.