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Volume:4 Issue:9 Number:4 ISSN#:2563-559X
OE Original

COVID-19 Vaccine: What Do We Know About Its Efficacy and Safety in Children?

Authored By: OrthoEvidence

September 27, 2021

How to Cite

OrthoEvidence. COVID-19 Vaccine: What Do We Know About Its Efficacy and Safety in Children?. OE Original. 2021;4(9):4. Available from: https://myorthoevidence.com/Blog/Show/150

Highlights


  • - The Pfizer/BioNTech mRNA vaccine is the first COVID-19 vaccine being approved for individuals 16 years of age and older by the United States Food and Drug Administration (US FDA). For children at the age of 12 through 15 years, the Pfizer/BioNTech Vaccine can still be administered under the FDA emergency use authorization. Evidence regarding the efficacy and safety of COVID-19 vaccines in children is still limited.


  • - On September 20, 2021, Pfizer and BioNTech announced their initial vaccine trial results for children aged 5 and 11 years. Trial data in children aged 6 months to 5 years can be expected later this year.


  • - Pfizer and BioNTech reported that the mRNA COVID-19 vaccine was well tolerated and the SARS-CoV-2–neutralizing antibody geometric mean titer in children aged 5 to 11 years and vaccinated with 2 doses of Pfizer/BioNTech mRNA COVID-19 vaccine was “non-inferior” to that in people aged 16 to 25 years and vaccinated with 2 doses of Pfizer/BioNTech vaccine.


  • - No significant differences were between adolescents aged 12 to 15 years who received vaccine vs. placebo in the incidence of reactogenicity or serious adverse events after receiving the Pfizer/BioNTech mRNA COVID-19 vaccine. The vaccine efficacy against COVID-19 occurring >= 7 days after the 2nd dose of the Pfizer/BioNTech mRNA COVID-19 vaccine in adolescents aged 12 to 15 years without evidence of SARS-CoV-2 infection prior to 7 days after the 2nd dose was 100%.


  • - The Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) concluded that the benefits (represented by prevention of COVID-19 disease and hospitalizations, intensive care unit admissions, and deaths) from the mRNA COVID-19 vaccines outweigh the risks (represented by expected myocarditis cases after vaccination) in all populations eligible for vaccination (Gargano et al., 2021).





To date, close to 6 billion doses of COVID-19 vaccine have been administered around the globe with approximately 43.3% of the world population having received at least 1 dose of COVID-19 vaccine (Our World in Data: COVID-19 Vaccinations).


Vaccines have saved numerous lives which would have been lost due to COVID-19. A study estimated that by early May 2021, the vaccination campaign in the United States (US) was associated with a reduction of about 140,000 COVID-19-related mortality, and the reduction in deaths has led to an economic value of between 625 billion and 1.4 trillion dollars (Gupta et al., 2021).


Among available vaccines on the market, the Pfizer/BioNTech vaccine (commercial name: Comirnaty) had recently become the first COVID-19 vaccine being approved for individuals 16 years of age and older by the United States Food and Drug Administration (US FDA). For children at the age of 12 through 15 years, the Pfizer/BioNTech Vaccine can still be administered under the FDA emergency use authorization (EUA).






“The FDA’s approval of this vaccine [Pfizer/BioNTech vaccine in people >= 16 years] is a milestone as we continue to battle the COVID-19 pandemic. While this and other vaccines have met the FDA’s rigorous, scientific standards for emergency use authorization, as the first FDA-approved COVID-19 vaccine, the public can be very confident that this vaccine meets the high standards for safety, effectiveness, and manufacturing quality the FDA requires of an approved product.


While millions of people have already safely received COVID-19 vaccines, we recognize that for some, the FDA approval of a vaccine may now instill additional confidence to get vaccinated...”


-- Janet Woodcock, Acting FDA Commissioner --






On September 20, 2021, Pfizer and BioNTech announced their vaccine clinical trial results obtained from children between the ages of 5 and 11 years. Pfizer and BioNTech are currently in the process of submitting their data to major regulatory health agencies such as the FDA and European Medicines Agency (EMA) for approval. If approved, this would be another milestone in our battle against the pandemic for it could enable us to extend the protection from COVID-19 vaccines to the young children.


In this OE Original, we examine current evidence regarding the efficacy and safety of COVID-19 vaccines in children, especially the latest evidence obtained from children between the ages of 5 and 11 years.





1. Trial data of the Pfizer/BioNTech vaccine in children (5-11 years old)


The Pfizer/BioNTech vaccine trial in children, a global seamless phase I/II/III trial carried out in over 90 clinical trial centers in Finland, Poland, Spain, and the US., were designed to determine the efficacy (i.e., immunogenicity), safety, and tolerability of the Pfizer/BioNTech mRNA vaccine against COVID-19 in children of 3 age groups: aged 6 months to 2 years, 2 to 5 years, and 5 to 11 years.


Currently, the trial data are available for children aged between 5 and 11 years, while the results for the other two age groups will be released in the 4th quarter of 2021. The basic information of the trial in children 5 to 11 years old are presented in Table 1.


Overall, the SARS-CoV-2–neutralizing antibody geometric mean titer (GMT) in children who were aged 5 to 11 years and vaccinated with 2 doses of Pfizer/BioNTech COVID-19 vaccine (10 ug per dose) was “non-inferior”* to that in people who were aged 16 to 25 years and vaccinated with 2 doses of Pfizer/BioNTech COVID-19 vaccine (30 ug per dose) (Table 1).


* The definition of noninferiority was not provided. In the trial in adolescents aged 12 to 15 years, Pfizer and BioNTech defined noninferiority as the lower bound of the 2-sided 95% CI for the SARS-CoV-2–neutralizing antibody GMT ratio (12 to 15 years / 16 to 25 years) was greater than 0.67.



In terms of safety and tolerability, no data were provided in the press release but Pfizer and BioNTech claimed that the COVID-19 vaccine was well tolerated in children aged 5 to 11 years. The side effects were generally comparable to those observed in individuals aged 16 to 25 years.



Table 1. Basic information of the Pfizer/BioNTech vaccine trials in children aged 5 to 11 years*

 

The Pfizer/BioNTech phase II/III trial

P (Participants)

Children who were 5 to 11 years of age in the intervention group;

Participants who were 16 to 25 years of age in the control group

No. of Participants

2268 in the intervention group;

No. of participants was not reported in the control group

I (Intervention)

Receiving Pfizer/BioNTech COVID-19 vaccine 10 µg per dose for 2 doses approximately 21 days apart

C (Comparator)

Receiving Pfizer/BioNTech COVID-19 vaccine 30 µg per dose for 2 doses approximately 21 days apart

O (Outcome) -- Efficacy

SARS-CoV-2–neutralizing antibody geometric mean titer (95% CI):

-- Children who were 5 to 11 years of age: 1197.6 (1106.1 to 1296.6)

-- Participants who were 16 to 25 years of age: 1146.5 (1045.5 to 1257.2)

No significant difference

O (Outcome) -- Safety and tolerability

Quotes: The COVID-19 vaccine was well tolerated [in children aged 5 to 11 years], with side effects generally comparable to those observed in participants 16 to 25 years of age

95% CI: 95% confidence interval * Limited information was available in the press release. Pfizer and BioNTech are planning to submit data for scientific peer-reviewed publication




2. Efficacy and safety results of the Pfizer/BioNTech vaccine in adolescents at the age of 12 through 15 years (The cut-off date for data assessment was March 13, 2021.)


The phase III trial, which enrolled 2260 adolescents 12 to 15 years of age in the US, found that the SARS-CoV-2–neutralizing antibody GMT 1 month after receiving the second dose of the Pfizer/BioNTech COVID-19 vaccine (30 ug per dose, approximately 21 days apart between 2 doses) in adolescents who were aged 12 to 15 years was “non-inferior”** to the GMT in individuals 16 to 25 years of age (FDA, Frenck et al., 2021) (Table 2).



** Noninferiority was defined as the lower bound of the 2-sided 95% CI for the SARS-CoV-2–neutralizing antibody GMT ratio (12 to 15 years / 16 to 25 years) was greater than 0.67.




Table 2. The SARS-CoV-2–neutralizing antibody geometric mean titer (GMT) results in adolescents aged 12 to 15 years*

 

GMT in Adolescents 12-15 Years (N = 190)

GMT in Participants 16-25 years (N = 170)

GMT Ratio (12-15 years/16-25 years)

One month after 2nd dose of Pfizer/BioNTech COVID-19 vaccine

1239.5

(95% CI: 1095.5 to 1402.5)

705.1

(95% CI: 621.4 to 800.2)

1.76

(95% CI: 1.47 to 2.10)

95% CI: 95% confidence interval; * The cut-off date for data assessment was March 13, 2021. 

The vaccine efficacy against COVID-19 occurring at least 7 days after the second dose of the Pfizer/BioNTech COVID-19 vaccine in adolescents aged 12 to 15 years without evidence of SARS-CoV-2 infection prior to 7 days after the second dose was 100% [0 cases in the vaccination group (N = 1001) vs. 16 cases in the placebo group (N = 972); 95% CI: 75.3% to 100%; Relative Risk (RR): 0.03, 95% CI: 0.00 to 0.49; quality of evidence determined by GRADE: High] (FDA).


The vaccine efficacy against confirmed SARS-CoV-2 infection occurring at least 7 days after the second dose of the Pfizer/BioNTech COVID-19 vaccine in adolescents aged 12 to 15 years with or without evidence of SARS-CoV-2 infection prior to and during vaccination regimen was 100% [0 cases in the vaccination group (N = 1109) vs. 18 cases in the placebo group (N = 1110), 95% CI: 78.1% to 100%] (FDA, Frenck et al., 2021).


In terms of serious adverse events, defined as death, life-threatening event, hospitalization, incapacity to perform normal life functions, medically important event, or congenital anomaly/birth defect, there was no statistically significant difference between adolescents aged 12 to 15 years who received vaccine vs. placebo (5/1131 in the vaccine group vs. 2/1129 in the placebo group; RR: 2.50, 95% CI: 0.49 to 12.84; quality of evidence determined by GRADE: Very low] (FDA).


In terms of reactogenicity, defined as local and systemic events (grade >= 3***), there was also no statistically significant difference between adolescents aged 12 to 15 years who received vaccine vs. placebo (121/1131 in the vaccine group vs. 22/1129 in the placebo group; RR: 5.49, 95% CI: 3.51 to 8.58; quality of evidence determined by GRADE: High] (FDA).


*** Grade 3: The event prevents daily routine activity or requires use of a pain reliever. Grade 4: The event requires an emergency room visit or hospitalization.





3. Other evidence regarding COVID-19 vaccines in children


Since June 2021, myocarditis and myopericarditis cases after receiving Pfizer/BioNTech vaccine have been reported especially among young males after the second dose (Shay et al., 2021). As a result, the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) later assessed the benefits and risks of receiving mRNA COVID-19 vaccines (Gargano et al., 2021).


ACIP concluded that the benefits (represented by prevention of COVID-19 disease and hospitalizations, intensive care unit admissions, and deaths) from the mRNA COVID-19 vaccines outweigh the risks (represented by expected myocarditis cases after vaccination) in all populations eligible for vaccination (Gargano et al., 2021). Specifically, 8500 COVID-19 cases, 183 hospitalizations, 38 intensive care unit admissions, and 1 death due to COVID-19 could be prevented, compared to 8 to 10 expected myocarditis cases after COVID-19 vaccination, per million second doses of mRNA COVID-19 vaccines administered to females aged 12 to 17 years (Gargano et al., 2021). Moreover, 5700 COVID-19 cases, 215 hospitalizations, 71 intensive care unit admissions, and 6 deaths could be prevented, compared with 56 to 69 expected myocarditis cases after COVID-19 vaccination, per million second doses of mRNA COVID-19 vaccines administered to males at the age of 12 to 17 years (Gargano et al., 2021).


To further characterize safety of the Pfizer/BioNTech COVID-19 vaccine, the Vaccine Adverse Event Reporting System (VAERS), a vaccine safety surveillance system managed by FDA and CDC, reported the safety results of the Pfizer/BioNTech COVID-19 vaccine in adolescents aged 12 to 17 years who received COVID-19 vaccines between December 2020 and July 2021(Hause et al., 2021). Hause et al. (2021) concluded that the safety findings of the Pfizer/BioNTech vaccine from VERS in the US adolescents aged 12 to 17 years are similar to those reported in clinical trials.


Specifically, during the period, 9246 adverse events, most of which were non-serious events (8383, 90.7%), were reported by VERS among approximately 8.9 million adolescents aged 12 to 17 years who had received a Pfizer/BioNTech COVID-19 vaccine during the study period (about 1 per 1000 vaccine recipients) (Hause et al., 2021). The most common event was dizziness (1862, 18.1%), followed by syncope (1228, 13.3%) and headache (1027, 11.1%) (Hause et al., 2021). The most common events among 863 serious adverse events reported were chest pain (56.4%), increased troponin levels (41.7%), myocarditis (40.3%), increased c-reactive protein (30.6%), and negative SARS-CoV-2 test results (29.4%) (Table 2); all of which indicated a diagnosis of myocarditis. Myocarditis accounted for about 4.3% (397/9246) of all VAERS reports (Hause et al., 2021).




Closing Remark


In this OE Original, we reviewed current evidence with regard to the efficacy and safety of COVID-19 vaccines in children. Evidence is relatively limited and focuses mainly on the mRNA COVID-19 vaccine developed by Pfizer/BioNTech. While data in children aged 6 months to 5 years can be expected later this year, available trial results suggest that the Pfizer/BioNTech mRNA COVID-19 vaccine is efficacious, safe, and tolerant in children aged 5 to 11 years or 12 to 15 years.





Reference


Frenck, R. W., Jr., et al. (2021). Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. The New England journal of medicine, 385(3), 239-250. doi:10.1056/NEJMoa2107456

Gargano, J. W., et al. (2021). Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021. MMWR Morb Mortal Wkly Rep, 70(27), 977-982. doi:10.15585/mmwr.mm7027e2

Gupta, S., et al. (2021). Vaccinations Against COVID-19 May Have Averted Up To 140,000 Deaths In The United States. Health Affairs, 40(9), 1465-1472. doi:10.1377/hlthaff.2021.00619

Hause, A. M., et al. (2021). COVID-19 Vaccine Safety in Adolescents Aged 12-17 Years - United States, December 14, 2020-July 16, 2021. MMWR. Morbidity and mortality weekly report, 70(31), 1053-1058. doi:10.15585/mmwr.mm7031e1

Shay, D. K., et al. (2021). Myocarditis Occurring After Immunization With mRNA-Based COVID-19 Vaccines. JAMA Cardiol. doi:10.1001/jamacardio.2021.2821


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