Recommendations on the use of Moderna Spikevax COVID-19 vaccine in children 6 months to 5 years of age

Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Background

The Moderna Spikevax (25 microgram [mcg] dose) mRNA COVID-19 vaccine is the first COVID-19 vaccine authorized in Canada for use in pediatric populations under the age of 5 years. Moderna Spikevax (25 mcg) was approved for children 6 months to 5 years of age on July 14, 2022. Prior to July 14, 2022, mRNA COVID-19 vaccines have been previously authorized by Health Canada in other pediatric populations (<12 years of age) as follows:

For further information on NACI's recommendations on the use of mRNA COVID-19 vaccines, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).

NACI's recommendations are aligned with the following goals of the Canadian COVID-19 Immunization Program, updated on February 14, 2022:

Methods

On June 7, 2022 and June 21, 2022, NACI reviewed the available evidence on the use of Moderna Spikevax (25 mcg) COVID-19 vaccine in children 6 months to 5 years of age. The body of evidence included manufacturer's clinical data in the regulatory submission to Health Canada, burden of COVID-19 disease in this population, and post-market safety data for other formulations of mRNA vaccines in older age groups. Ethical considerations related to COVID-19 vaccination in pediatric populations aged ≤ 12 years were discussed with the Public Health Ethics Consultative Group (PHECG) on May 3, 2021, July 6, 2021, September 21, 2021, and May 12, 2022. The Canadian Immunization Committee (CIC) provided feedback on key policy questions to ensure alignment with provincial/territorial program needs on April 28, 2022. NACI approved their recommendations on the use of Moderna Spikevax in children 6 months to 5 years of age on July 6, 2022.

Details of NACI's evidence-informed recommendation development process can be found elsewhereFootnote 1,Footnote 2.

Summary of evidence

COVID-19 burden of disease in children

The majority of children with COVID-19 have mild or asymptomatic disease; however, some children get severe disease and require hospitalization. Population level estimates of hospitalization and ICU admission in pediatric populations have increased since Omicron became the predominant variant. For children 6 months to 4 years of age (the age group previously ineligible for COVID-19 immunization), the average monthly rate of hospitalization due to COVID-19 increased from 1.4 to 15.9 per 100,000, comparing March 1, 2020 - December 31, 2021 to January 1, 2022 – March 31, 2022Footnote 3. This analysis includes data from 6 of Canada's 13 provinces and territories that provide surveillance data to PHAC that includes age in months for pediatric cases. Increased COVID-19 associated hospitalization rates across pediatric populations are consistent with increased seroprevalence rates across older age groups and the overall increase in reported cases across the population since Omicron became the predominant variant.

Canadian seroprevalence studies from Quebec (January 26, 2022 ─ February 17, 2022) and British Columbia (BC) from March 2022 estimate that 30% to 70% of children under the age of 5 years have been previously infected with SARS-CoV-2; most of these infections occurred since Omicron became the dominant variantFootnote 4,Footnote 5,Footnote 6. These data may not be generalizable to other regions of Canada though, and national COVID-19 seroprevalence estimates are unknown in children 5 years of age or younger.

Multisystem inflammatory syndrome in children and post-COVID-19 condition in children

Children who have had COVID-19 are at risk of multisystem inflammatory syndrome in children (MIS-C), a rare but serious post-infection complication that generally requires acute care hospital admission. Out of 419 nationally reported cases of MIS-C in Canada, no deaths have been reported to dateFootnote 7. MIS-C associated deaths have been reported in the United States (US)Footnote 8; however, the generalizability of this data to the Canadian healthcare system is unknown.

While evidence is limited in children 5 years of age and younger, SARS-CoV-2 infection may lead to post-COVID condition/post-acute COVID syndrome. This evidence is evolving for younger (<12 years) pediatric age groups.

For more information on MIS-C and other signs and symptoms of COVID-19 or post-infection complications, please refer to COVID-19 signs, symptoms and severity of disease: A clinician guide.

Risk factors most frequently associated with severe disease in children 5 years of age and younger

A rapid review on the magnitude of association between risk factors and severe outcomes of COVID-19 in children 5 years of age and younger was conducted by COVID-END (last updated on March 7, 2022)Footnote 9. Children ≤5 years of age with any comorbidity may have an increased risk for severe COVID-19 outcomes (n=6 studies; moderate certainty of evidence)Footnote 10,Footnote 11,Footnote 12. The evidence suggesting that race and ethnicity and/or living with social and structural inequities are risk factors for severe COVID-19 outcomes (n= 2 studies) is limited (very low certainty of evidence)Footnote 11,Footnote 15. Five studies assessed the relationship between specific comorbidities and severe outcomes in children aged 0 to 2 months and 3-5 months. A number of risk factors had statistically significant associations with severe COVID-19 outcomes, including cardiac and circulatory congenital anomalies; chronic lung conditions; and feeding tube dependenceFootnote 11,Footnote 12,Footnote 13. For children <2 years, statistically significant associations for severe disease were reported for prematurity, cardiovascular condition, respiratory condition, abnormality of airways, neurologic disorder, feeding tube dependence and hypertension. For children 2 to 5 years, statistically significant associations with severe disease were reported for neurodevelopmental disorders, epilepsy and/or convulsions, obesity, chronic metabolic disease and immunosuppressionFootnote 13,Footnote 16,Footnote 17. However, the majority of studies conducted to inform on the risk factors of severe outcomes of COVID-19 in pediatric populations occurred pre-Omicron and may not be generalizable to the current epidemiologic situation across CanadaFootnote 9.

The severity of disease for future SARS-CoV-2 variants in children or any other population is unknown.

Clinical trial data on Moderna Spikevax (25 mcg) in children 6 months to 5 years of age

The Moderna Spikevax COVID-19 vaccine was evaluated in pediatric participants aged 6 months to 5 years as part of an ongoing, Phase 2/3, randomized, observer-blind, placebo-controlled study. For all analyses, the participants were split into two age-based subgroups; ages 6 to 23 months and 2 to 5 years. Participants were recruited from the US and Canada beginning November 2021 and enrollment is ongoing. Participants were randomly assigned to receive either two doses of the vaccine (25 mcg mRNA) or two doses of a placebo, administered 28 days apartFootnote 18.

Across both age groups and between the vaccine and placebo groups, approximately 50% of participants were female. Among participants that received the Moderna Spikevax vaccine, the majority were between 1 and <5 years of age, whereas about 8% were aged 6 months to 11 months and about 2% were age 5 years to < 6 yearsFootnote 19.

At data cut-off (February 21, 2022), median follow up after the second dose was 68 days for participants aged 6 to 23 months and median follow up time was 72 days for participants aged 2 years to 5 years.

Efficacy

Vaccine efficacy was assessed among children aged 6 months to 5 years following one and two doses of Moderna Spikevax (25 mcg) mRNA COVID-19 vaccine during a time when Omicron was the predominant variant of SARS-CoV-2 in the US and Canada (data cut-off February 21, 2022)Footnote 18. The per-protocol population (negative baseline SARS-CoV-2 status and received two doses of either vaccine or placebo) included 5,476 participants who received two doses of either vaccine or placebo (for participants 6 months through 23 months, 1,511 participants in the vaccine group, 513 in the placebo group; for participants 2 years through 5 years, 2,594 in the vaccine group, 858 in the placebo group)Footnote 20.

Efficacy estimates among participants without evidence of prior SARS-CoV-2 infection (per-protocol population)

Efficacy against confirmed symptomatic SARS-CoV-2 infection starting 14 days after dose 2 was estimated at 50.6% (95% confidence interval [CI]: 21.4 to 68.6%) among study participants aged 6 to 23 months and 36.8% (95% CI: 12.5 to 54.0%) among participants aged 2 to 5 yearsFootnote 18,Footnote 20.

Efficacy against asymptomatic SARS-CoV-2 infection starting 14 days after dose 2 was estimated at 3.8% among study participants aged 6 to 23 months and 22.9% among participants aged 2 to 5 years; however, in both age groups, the confidence interval around the point estimate was wide and included zero (95% CI: -111.5 to 52.8% and 19.5 to 49.3%, respectively)Footnote 18,Footnote 20.

The estimate of vaccine efficacy against asymptomatic infection after 2 doses should be interpreted with caution as cases were identified among participants that were seronegative at baseline prior to dose 1 and who later had a positive reverse transcription polymerase chain reaction (RT-PCR) test or serology result at varying time points starting 14 days after dose 2; however, there was a limited number of participants providing samples for serology at later time points. Therefore, this finding could reflect infection acquired at any time after dose 1 prior to the time of sample collection, and may be an underestimation of 2 dose efficacy.

Efficacy against confirmed symptomatic SARS-CoV-2 infection from 14 days after dose 1 until dose 2 was estimated at -11.4% among study participants aged 6 to 23 months and 17% among participants aged 2 to 5 years. However, estimates of 1-dose vaccine efficacy should be considered with caution, as few cases were reported during this two-week time frame, and accordingly the confidence interval around the point estimate was wide and included zero (95% CI: -529.8 to 71.3% and -161.2 to 69.6%, respectively)Footnote 21,Footnote 22.

Efficacy estimates among participants with or without evidence of prior SARS-CoV-2 infection

Efficacy against confirmed symptomatic SARS-CoV-2 infection starting 14 days after dose 2 was also determined among participants regardless of evidence of prior to SARS-CoV-2 infection and was estimated at 50.6% (95% CI: 21.4 to 68.6%) among study participants aged 6 to 23 months and 36.5% (95% CI: 12.5 to 54.0%) among participants aged 2 to 5 yearsFootnote 23.

Efficacy estimates against severe outcomes of COVID-19

There were no deaths or cases of severe COVID-19 or MIS-C among trial participants that received the vaccine; however, one case of MIS-C was reported after the February 21, 2022 data cut-off in a participant that received the placeboFootnote 18. Therefore, efficacy against outcomes of severe COVID-19 or MIS-C was not evaluated.

Real world evidence suggests mRNA vaccines in older age groups have high vaccine effectiveness (VE) at preventing severe outcomes of COVID-19 including hospitalization and death. Additionally, mRNA vaccines have high VE against hospitalization due to MIS-C in adolescent populationsFootnote 24.

Estimates of Moderna Spikevax vaccine efficacy against symptomatic disease during the Omicron wave in children aged 6 months to 5 years are consistent with VE reported for Pfizer-BioNTech Comirnaty (10 mcg) vaccine among children 5 to 11 years of age during the Omicron waveFootnote 25. However, waning of immune responses over time are well documented in older age groups and may also contribute to lower VE estimates when calculating VE at longer intervals following vaccination or infection. VE against any future variants is unknown.

For further information on the VE of mRNA COVID-19 vaccines against severe outcomes of COVID-19 including hospitalization due to MIS-C, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).

Immunogenicity

Immunogenicity as per protocol among participants without evidence of prior SARS-CoV-2 infection

The humoral immune response to Moderna Spikevax (25 mcg) was non-inferior in children aged 6 months to 5 years compared to young adults, meeting pre-established non-inferiority criteria (lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] >0.67; point estimate ≥0.8). SARS-CoV-2 neutralizing antibody titers (ID50) were assayed 28 days following dose 2, and the GMR of neutralizing antibody titres in children 2 to 5 years of age (n=264) and 6 to 23 months of age (n=230) relative to young adults (18 to 25 years of age; n=291) was 1.01 (95% CI: 0.88 to 1.17%) and 1.280 (95% CI: 1.12 to 1.47%), respectively. The neutralizing seroresponse rates (SRR) among children 2 to 5 years and children 6 to 23 months old were 98.9% and 100% respectively, with differences compared to young adults of -0.4% (95% CI: -2.7 to 1.5%) and 0.7% (95% CI: -1.0 to 2.5%), respectively, meeting non-inferiority success criteria (lower bound of the 95% CI of the SRR difference > -10%)Footnote 20.

Immunogenicity in participants based on SARS-CoV-2 serology at baseline

Approximately 9% of participants 2 to 5 years of age and 6% of participants 6 to 23 months of age had serologic evidence of prior SARS-CoV-2 infection at the start of the study and were thus excluded from immunobridging analysesFootnote 18. Neutralizing antibody titres increased in these participants 28 days after dose 2. In seropositive children 2 to 5 years of age, antibody titres increased by 37-fold compared to pre-vaccination titres. In seropositive children 6 to 23 months of age, antibody titres increased by 49-fold compared to pre-vaccination titresFootnote 26. Antibody titres for seropositive children aged 2 to 5 years and 6 to 23 months were at least 4- or 6-fold higher 28 days after dose 2 compared to seronegative children.

In both seronegative and seropositive participants, antibody titres were generally higher in children 6 to 23 months of age compared to children 2 to 5 years of age.

As an immunological correlate of protection has not been determined for COVID-19 at this time, it is unknown how the immune response levels that have been reported in clinical trials are related to the prevention of SARS-COV-2 infection or disease or the ability to transmit to others.

Safety

The Moderna Spikevax (25 mcg) COVID-19 vaccine was well tolerated in children aged 6 months to 5 years. Safety data were collected in a still ongoing Phase 2/3 clinical trial that included children 6 months through 5 years of age. The safety data analyzed was based on a February 21, 2022 data cut-off. At the time of data cut-off, the safety analysis set included 375 subjects who were 6 months to < 1 year of age, 1,373 subjects who were 1 to < 2 years of age, and 3,007 subjects who were 2 to < 6 years of ageFootnote 20. No safety signals were identified after a median of 103 days after dose 1 and 71 days after dose 2 for ages 2 to 5 years, and 98 days after dose 1 and 68 days after dose 2 for children 6 months to < 2 years of age. Duration of participant follow-up ranged from 0 to 127 days after dose 1 and from 0 to 99 days after dose 2 as the study was still recruiting participants at time of data cut offFootnote 18.

Overall, the safety profile of Moderna Spikevax (25 mcg) vaccine was consistent with the known safety and reactogenicity profile of the 50 mcg and 100 mcg Spikevax formulations authorized for use in older age groups. Events reported in the vaccine group were consistent with events commonly reported for other pediatric vaccines authorized for use in children 6 months to 5 years of age.

Local and systemic adverse events

Data on solicited local and systemic adverse reactions included 4,792 participants 6 months to 5 years of age who received at least one dose of vaccine, and 1,596 participants who received at least one dose of placebo. Solicited local adverse reactions within 7 days, including grade 3 events, were reported at a higher frequency in the vaccine group than in the placebo group in both the 2 to 5 year and the 6 months to < 2 year age groups, particularly after the second dose. Solicited systemic adverse reactions within 7 days reported after dose 1 were similar when compared to placebo in both age groups, but were reported at a higher frequency in the vaccine group than in the placebo group after the second dose, including grade 3 events. The majority of solicited local and systemic adverse reactions were grade 1 or 2 and occurred within the first 2 days after any dose of vaccine and persisted for a median of 2 to 3 days. The incidence of grade 3 solicited adverse reactions was infrequent in both vaccine and placebo groups in both age groups (< 5% after any dose)Footnote 20.

The most frequently reported solicited local and systemic adverse reactions were irritability/crying, pain, sleepiness, and loss of appetite. Fatigue (48.4%) was the most frequently reported systemic adverse reaction in the participants 37 months to 5 years of ageFootnote 20.

See Table 1 of the Appendix for the frequency of solicited local adverse events (AEs) for the Moderna Spikevax COVID-19 vaccine among children 6 months to 5 years of age.

Any type of AE that occurred in at least 1% of study participants aged 6 months to <2 years of age who received vaccine and at a rate at least 1.5-fold higher than in the placebo group, included acute otitis media (1.4% versus 0.7%), injection site lymphadenopathy (1.4% versus 0.2%) and injection site erythema (1.1% versus 0.2%). In children 2 to 5 years of age, only injection site erythema occurred in ≥ 1% in the vaccine arm and at a rate at least 1.5-fold higher than placebo (1.3% versus 0.2%)Footnote 18.

Serious adverse events and other adverse events of interest

For participants 2 to 5 years of age: Serious adverse events (SAEs) up to and beyond 28 days since last dose were reported at a frequency of 0.3% (n=9) for the vaccine group and 0.2% (n=2) for the placebo group. None of the reported SAEs were considered related to the vaccineFootnote 20. The incidence of medically attended events up to 28 days after any dose was similar in the vaccine group (662/3031; 21.8%) compared with the placebo group (221/1007; 21.9%). No participants in either group discontinued the study due to an adverse eventFootnote 18.

For participants 6 months to <2 years of age: SAEs up to and beyond 28 days since last dose were reported at a frequency of 0.9% (n=15) for the vaccine group and 0.2% (n=1) for the placebo group. In the vaccine group, there was 1 participant with two SAEs considered related to the vaccine (a grade 3 fever that occurred 6 hours after dose 1, which was followed by a febrile convulsion).  None of the other reported SAEs were considered related to the vaccineFootnote 20. The incidence of medically attended events up to 28 days after any dose were also similar in the vaccine group (486/1761; 27.6%) compared with the placebo group (161/589; 27.3%). One participant in each group discontinued study vaccinationFootnote 18.

There was 1 event of anaphylaxis attributed to a concurrent medication in the 2 to 5 year age group (32 days after vaccination), and 2 events of egg or food product related-anaphylaxis unrelated to the vaccine in the younger age group 6 months to < 2 years (15 and 18 days after vaccination)Footnote 18
There were no deaths, no cases of MIS-C, and no cases of myocarditis and/or pericarditis reported in any participant during the study periodFootnote 18. Given the trial was limited to n=4,792 participants randomized to receive the Moderna Spikevax (25 mcg) vaccine, it is unlikely that any AE occurring at a frequency less often than 6 in 10,000 would be detected.

Canadian and international post-market safety surveillance data for other mRNA COVID-19 vaccines in older populations have reported the rare risk of myocarditis and/or pericarditis with mRNA vaccines, which varies by sex, age, interval between doses, vaccine dose, and vaccine product. Current data suggests the risk of myocarditis and/or pericarditis in younger children is lower than that of adolescents or young adults. 

For further information on the risk of myocarditis and/or pericarditis following vaccination with an mRNA COVID-19 vaccine, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).  

Vaccine

COVID-19 vaccine preparations authorized for use among pediatric populations 6 months to 5 years of age in Canada

Table 1. Use of COVID-19 vaccines for children 6 months to 5 years of age
Product characteristics Moderna Spikevax

Age

6 months to 5 years

Dose

25 mcg (0.25 mL)

Presentation

0.10 mg/mL
Royal blue vial cap

Diluent

None

Potential allergens

Polyethylene glycol (PEG), Tromethamine (trometamol or Tris)Footnote a

StorageFootnote b,Footnote c

  • Store at temperatures of -50°C to -15°C and protect from light in original packaging
  • Vials can be thawed and stored at +2°C to +8°C for up to 30 days, or at +8°C to +25°C for up to 24 hours if unpunctured
  • Do not refreeze once thawed

TransportFootnote c

If transport at -50° to -15°C is not feasible, thawed vials in a liquid state may be transported at +2°C to +8°C for up to 12 hours.

Table 1 Footnote a

Tromethamine (Tris or trometamol) is used as a buffer in vaccines and medications, including those for use in children, to improve stability and prevent pH fluctuations in the solution. No safety concerns have been identified with tromethamine. While tromethamine has been identified as a potential allergen, a review of existing evidence did not identify any cases of allergic reactions to tromethamine in childrenFootnote 27.

Table 1 Return to footnote a referrer

Table 1 Footnote b

Regardless of storage condition, vaccines should not be used after date of expiry printed on the vial and cartons.

Table 1 Return to footnote b referrer

Table 1 Footnote c

Frozen is -25°C to -15°C; Refrigerated is +2°C to +8°C; Room temperature is +15°C to +25°C.

Table 1 Return to footnote c referrer

For complete prescribing information for the pediatric and adult formulations of Moderna Spikevax COVID-19 vaccine, please refer to the product leaflets or information contained within Health Canada's authorized product monographs available through the Drug Product Database.

Schedule

Refer to Table 2 for a summary of immunization schedules for authorized COVID-19 vaccines among children 6 months to 5 years of age.

Table 2. Immunization schedule for primary series, by COVID-19 vaccine
Vaccine product Age Dose Immunization schedule Authorized interval NACI - Recommended intervalFootnote 1,

Moderna Spikevax (25 mcg)

6 months to 5 years

25 mcg (0.25 mL)

2-dose schedule

28 days

At least 8 weeks

Pfizer-BioNTech Comirnaty (10 mcg)

5 to 11 years

10 mcg (0.2mL)

2-dose schedule

21 days

At least 8 weeks

Table 2 Footnote 1

There is emerging evidence that longer intervals between the first and second doses of COVID-19 vaccines result in more robust and durable immune response and higher VE. Data from older age groups also suggests an extended interval may be associated with a reduced risk of myocarditis/pericarditis following a second dose of an mRNA COVID-19 vaccine. NACI will continue to monitor the evidence and update this interval as needed.

Table 2 Return to footnote 1 referrer

Recommendations

For children 6 months to 5 years of age (which is the age group in which the Moderna Spikevax 25 mcg primary series vaccine is authorized): 

  1. NACI recommends that a complete series with the Moderna Spikevax (25 mcg) COVID-19 vaccine may be offered to children 6 months to 5 years of age who do not have contraindications to the vaccine, with a dosing interval of at least 8 weeks between the first and second dose. (Discretionary NACI Recommendation)
  2. NACI recommends that children 6 months to 5 years of age who are moderately to severely immunocompromised may be immunized with a primary series of three doses of the Moderna Spikevax (25 mcg) vaccine, using an interval of 4 to 8 weeks between each dose. (Discretionary NACI Recommendation)
  3. NACI recommends at this time that the Moderna Spikevax (25 mcg) COVID-19 vaccine primary series for children 6 months to 5 years of age should not routinely be given concurrently (i.e., same day) with other vaccines (live or non-live). (Strong NACI recommendation)
  1. For children 5 years of age (the age group in which both the Moderna Spikevax (25 mcg) and the Pfizer-BioNTech Comirnaty (10 mcg) COVID-19 vaccine primary series are authorized):
    • 4.1  Moderna Spikevax (25 mcg) may be offered to children 5 years of age as an alternative to Pfizer-BioNTech Comirnaty (10 mcg); however, the use of Pfizer-BioNTech Comirnaty (10 mcg) is preferred to Moderna Spikevax (25 mcg). (Discretionary NACI Recommendation)
    • 4.2  Children who have received Moderna Spikevax (25 mcg) for a previous dose and turn 6 prior to completing their primary series are recommended to receive Moderna Spikevax (50 mcg) to complete their primary series. If the primary series was completed with Moderna Spikevax (25 mcg) or with Pfizer-BioNTech Comirnaty (10 mcg), the dose should be considered valid and the series complete. (Discretionary NACI Recommendation)

Considerations on when to offer the Moderna Spikevax (25 mcg) primary series to children 6 months to 5 years of age who have been previously infected with SARS-CoV-2:

Summary of evidence, and additional considerations

Research priorities

Additional information

NACI continues to endeavour to make ethical, equitable and evidence-informed recommendations. Given the paucity of data on benefits and risks of Imvamune® in the context of a monkeypox outbreak setting, the use of Imvamune® must balance the benefits and risks of what is known and unknown about the vaccine and the disease.

It is important to obtain informed consent when offering the vaccine, and to clearly explain to potential recipients what is unknown (in addition to what is known) about the vaccine, when discussing potential risks and benefits. This is particularly important for individuals identified by NACI as special populations and for any off-label use in individuals <18 years of age.

Additionally, there is an ethical obligation to conduct close monitoring and surveillance of the use of the vaccine, in order to collect information to inform the response going forward. While both informed consent and post-market safety surveillance will be vital for the ethical implementation of an Imvamune® vaccination program, especially in pediatric populations <18 years of age when the vaccine is being used off-label.

It will be important to closely monitor who is at risk of monkeypox and provide rationale for when vaccination is needed. Additionally, to prevent stigmatization of specific populations and potentially increase vaccine acceptability, the primary focus should be identifying risk factors for transmission of monkeypox (e.g., proximity of contact, sexual activities, specific behaviours) whenever possible, rather than identifying populations perceived to be at a higher risk.

Given the limited clinical evidence on the use of Imvamune® for monkeypox PEP or PrEP, understanding of the need for, and benefit of, Imvamune® in the context of a monkeypox outbreak setting is evolving.

Certain behaviours place individuals at increased risk of exposure to the monkeypox virus (e.g., proximity of contact, sexual activities, household member or behaviors that cause exposure to body fluids or fomites). Some populations are at increased risk of severe monkeypox disease due to various biological (e.g. individuals who are immunocompromised, pregnant, and/or, young children) and social factors that may intersect. Risk factors of severe disease and risk of exposure may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection, disease, and severe illness. Program planning should ensure equitable access to vaccination information and services and minimize differences in vaccine acceptance and uptake based on socioeconomic status and other socioeconomic determinants of health that may intersect.

Research Priorities

Abbreviations

AE
Adverse events
CI
Confidence Interval
CIC
Canadian Immunization Committee
COVID-19
Coronavirus disease 2019
GMR
Geometric mean ratio
ICU
Intensive Care Unit
IM
Intramuscular
MIS-C
Multisystem Inflammatory Syndrome in Children
mRNA
Messenger Ribonucleic Acid
NACI
National Advisory Committee on Immunization
PEG
Polyethylene glycol
PHAC
Public Health Agency of Canada
PHECG
Public Health Ethics Consultative Groups
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SRR
Seroresponse rate
US
United States
VE
Vaccine effectiveness

Acknowledgements

This statement was prepared by: N Forbes, M Salvadori, R Pless, R Krishnan, N Abraham, A Killikelly, C Jensen, S Ismail, J Zafack, M Tunis, R Harrison, and S Deeks on behalf of NACI.

NACI gratefully acknowledges the contribution of: N St-Pierre, K Ramotar, C Mauviel, SH Lim, E Tarrataca, N Alluqmani, A Tuite, and the NACI Secretariat.

NACI members: S Deeks (Chair), R Harrison (Vice-Chair), M Andrew, J Bettinger, N Brousseau, H Decaluwe, P De Wals, E Dubé, V Dubey, K Hildebrand, K Klein, M O'Driscoll, J Papenburg, A Pham-Huy, B Sander, and S Wilson.

Liaison representatives: L Bill (Canadian Indigenous Nurses Association), LM Bucci (Canadian Public Health Association), E Castillo (Society of Obstetricians and Gynaecologists of Canada), A Cohn (Centers for Disease Control and Prevention, United States), J Comeau (Association of Medical Microbiology and Infectious Disease Control), L Dupuis (Canadian Nurses Association), E Adams (Indigenous Physicians Association of Canada), J Hu (College of Family Physicians of Canada), M Lavoie (Council of Chief Medical Officers of Health), D Moore (Canadian Paediatric Society), M Naus (Canadian Immunization Committee), and A Ung (Canadian Pharmacists Association).

Ex-officio representatives: V Beswick-Escanlar (National Defence and the Canadian Armed Forces), E Henry (Centre for Immunization and Respiratory Infectious Diseases (CIRID), PHAC), M Lacroix (Public Health Ethics Consultative Group, PHAC), C Lourenco (Biologic and Radiopharmaceutical Drugs Directorate, Health Canada), D MacDonald (COVID-19 Epidemiology and Surveillance, PHAC), S Ogunnaike-Cooke (CIRID, PHAC), K Robinson (Marketed Health Products Directorate, HC), M Routledge (National Microbiology Laboratory, PHAC), and T Wong (First Nations and Inuit Health Branch, Indigenous Services Canada).

NACI High Consequence Infectious Disease Working Group Members: R Harrison (Chair), N Brousseau, Y-G Bui, S Deeks, K Dooling, K Hildebrand, M Miller, and J Papenburg.

PHAC participants: NK Abraham, N Alluqmani, L Coward, N Forbes, C Jensen, CY Jeong, A Killikelly, R Krishnan, SH Lim, N Mohamed, J Montroy, A Nam, S Pierre, R Pless, M Salvadori, A Sinilaite, A Stevens, E Tice, A Tuite, MC Tunis, E Wong, R Ximenes, MW Yeung, J Zafack.

Appendix A: Frequency of solicited adverse events following immunization with Moderna Spikevax (25 mcg) in clinical trials

Table 1. Solicited local adverse reactions within 7 days after first and second injection by grade, 6 months to 23 months of age for the Moderna Spikevax (25 mcg) COVID-19 vaccineFootnote a,Footnote b
Adverse reactions Dose 1 Dose 2
Vaccine group
(N = 1746) n (%)
PlaceboFootnote a
(N = 582) n (%)
Vaccine group
(N = 1596) n (%)
Placeboa
(N = 526) n (%)
Pain
Any 652 (37.4) 175 (30.1) 738 (46.2) 135 (25.7)
Grade 3Footnote b 0 (0) 0 (0) 0 (0) 0 (0)
Erythema (redness)
Any 150 (8.6) 24 (4.1) 215 (13.5) 20 (3.8)
Grade 3Footnote c 5 (0.3) 2 (0.3) 13 (0.8) 0 (0)
Swelling (hardness)
Any 146 (8.4) 15 (2.6) 243 (15.2) 11 (2.1)
Grade 3Footnote c 5 (0.3) 0 (0) 14 (0.9) 0 (0)
Axillary (or groin) swelling or tenderness
Any 102 (5.9) 26 (4.5) 148 (9.3) 28 (5.3)
Grade 3Footnote b 0 (0) 0 (0) 0 (0) 0 (0)

n= # of participants with specified reaction, percentages are based on n/N.
N= number of exposed subjects who submitted any data for the event.

Table 1 Footnote a

Placebo was a saline solution.

Table 1 Return to footnote a referrer

Table 1 Footnote b

Grade 3 pain and axillary swelling/tenderness: Defined as prevents daily activity.

Table 1 Return to footnote b referrer

Table 1 Footnote c

Grade 3 swelling and erythema: Defined as >50 mm / >5 cm

Table 1 Return to footnote c referrer

The information in this table is up to date as of July 14, 2022. For updated information, please consult the SPIKEVAX product monograph.


Table 2. Solicited local adverse reactions within 7 days after first and second injection by grade, participants 2 to < 6 years of age
Adverse reactions Dose 1 Dose 2
Vaccine group
(N = 2957) n (%)
PlaceboFootnote a
(N = 970) n (%)
Vaccine group
(N = 2938) n (%)
PlaceboFootnote a
(N = 959) n (%)
Pain
Any 1813 (61.4) 382 (39.4) 2099 (71.4) 395 (41.2)
Grade 3Footnote b 4 (0.1) 0 (0) 11 (0.4) 0 (0)
Erythema (redness)
Any 164 (5.5) 14 (1.4) 259 (8.8) 15 (1.6)
Grade 3Footnote c 12 (0.4) 3 (0.3) 12 (0.4) 0 (0)
Swelling (hardness)
Any 134 (4.5) 17 (1.8) 240 (8.2) 11 (1.1)
Grade 3Footnote c 10 (0.3) 2 (0.2) 13 (0.4) 0 (0)
Axillary (or groin) swelling or tenderness
Any 205 (6.9) 56 (5.8) 267 (9.1) 31 (3.2)
Grade 3Footnote b 0 (0) 0 (0) 1 (< 0.1) 0 (0)
Use of antipyretic or analgesic medicationsFootnote d 498 (16.8) 121 (12.5) 800 (27.2) 105 (10.9)

n= # of participants with specified reaction, percentages are based on n/N.
N= number of exposed subjects who submitted any data for the event.

Table 2 Footnote a

Placebo was a saline solution.

Table 2 Return to footnote a referrer

Table 2 Footnote b

Grade 3 pain and axillary swelling/tenderness: Defined as prevents daily activity.

Table 2 Return to footnote b referrer

Table 2 Footnote c

Grade 3 swelling and erythema: Defined as >100 mm / >10 cm

Table 2 Return to footnote c referrer

Table 2 Footnote d

Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary).

Table 2 Return to footnote d referrer

The information in this table is up to date as of July 14, 2022. For updated information, please consult the SPIKEVAX product monograph.

Table 3. Solicited systemic adverse reactions within 7 days after first and second Injection by grade, participants 6 months to 23 months of age
Adverse reactions Dose 1 Dose 2
Vaccine group
(N =1746) n (%)
PlaceboFootnote a
(N = 582) n (%)
Vaccine group
(N =1596) n (%)
PlaceboFootnote a
(N =526) n (%)
Fever
Any 191 (11.0) 49 (8.4) 232 (14.6) 44 (8.4)
Grade 3 (≥39.6°C to ≤40°C) 11 (0.6) 3 (0.5) 7 (0.4) 6 (1.1)
Grade 4 (>40.0°C) 1 (<0.1) 1 (0.2) 3 (0.2) 0 (0)
Use of antipyretic or analgesic medicationsFootnote c 482 (27.6) 141 (24.2) 543 (34.0) 111 (21.1)
Irritability/crying
Any 1175 (67.6) 361 (62.1) 1021 (64.3) 307 (58.5)
Grade 3Footnote b 24 (1.4) 6 (1.0) 25 (1.6) 5 (1.0)
Sleepiness
Any 645 (37.1) 217 (37.3) 558 (35.1) 175 (33.3)
Grade 3Footnote b 4 (0.2) 1 (0.2) 1 (< 0.1) 1 (0.2)
Loss of appetite
Any

524 (30.2)

152 (26.2)

510 (32.1)

132 (25.1)

Grade 3Footnote b

10 (0.6)

1 (0.2)

16 (1.0)

2 (0.4)

n= # of participants with specified reaction, percentages are based on n/N.
N= number of exposed subjects who submitted any data for the event.

Table 3 Footnote a

Placebo was a saline solution.

Table 3 Return to footnote a referrer

Table 3 Footnote b

Grade 3 pain and axillary swelling/tenderness: Defined as prevents daily activity.

Table 3 Return to footnote b referrer

Table 3 Footnote c

Events and use of antipyretic or pain medication were collected in the electronic diary (e-diary).

Table 3 Return to footnote c referrer

The information in this table is up to date as of July 14, 2022. For updated information, please consult the SPIKEVAX product monograph.

Table 4. Solicited systemic adverse reactions within 7 days after first and second injection by grade, participants 24 months to ≤ 36 months of age
Adverse reactions Dose 1 Dose 2
Vaccine group
(N =944) n (%)
PlaceboFootnote a
(N = 320) n (%)
Vaccine group
(N =963) n (%)
PlaceboFootnote a
(N =330) n (%)
Fever
Any 106 (11.3) 25 (7.8) 182 (18.9) 35 (10.6)
Grade 3
(≥39.6°C to ≤40°C)
3 (0.3) 3 (0.3) 12(1.2) 0 (0)
Grade 4
(>40.0°C)
3 (0.3) 1 (0.3) 3 (0.3) 0 (0)
Irritability/crying
Any 513 (54.5) 163 (51.1) 523 (54.3) 148 (44.8)
Grade 3Footnote b 12 (1.3) 6 (1.9) 10 (1.0) 2 (0.6)
Sleepiness
Any 285 (30.3) 92 (28.8) 347 (36.0) 89 (27.0)
Grade 3Footnote b 2 (0.2) 0 (0) 1 (0.1) 0 (0)
Loss of appetite
Any 225 (23.9) 71 (22.3) 294 (30.5) 69 (20.9)
Grade 3Footnote b 7 (0.7) 1 (0.3) 8 (0.8) 0 (0)

n= # of participants with specified reaction, percentages are based on n/N.
N= number of exposed subjects who submitted any data for the event.

Table 4 Footnote a

Placebo was a saline solution.

Table 4 Return to footnote a referrer

Table 4 Footnote b

Grade 3 irritability/crying, sleepiness and loss of appetite: Defined as prevents daily activity.

Table 4 Return to footnote b referrer

The information in this table is up to date as of July 14, 2022. For updated information, please consult the SPIKEVAX product monograph.

Table 5. Solicited systemic adverse reactions within 7 days after first and second injection by grade, participants 37 months to < 6 years of age
Adverse reactions Dose 1 Dose 2
mRNA-1273
(N = 2013) n (%)
PlaceboFootnote a
(N = 650) n (%)
Vaccine group
(N = 2938) n (%)
PlaceboFootnote a
(N = 959) n (%)
Fever
Any 155 (7.7) 33 (5.1) 316 (16.0) 28 (4.5)
Grade 3 (≥39°C to ≤40°C) 23 (1.1) 4 (0.6) 58 (2.9) 2 (0.3)
Grade 4 (>40.0°C) 1 (<0.1) 1 (0.2) 4 (0.2) 0 (0)
Headache
Any 232 (11.5) 78 (12.0) 310 (15.7) 51 (8.1)
Grade 3Footnote b 5 (0.2) 2 (0.3) 8 (0.4) 1 (0.2)
Fatigue
Any 807 (40.1) 236 (36.3) 956 (48.4) 185 (29.4)
Grade 3Footnote b 21 (1.0) 11 (1.7) 45 (2.3) 8 (1.3)
Myalgia
Any 200 (9.9) 60 (9.2) 310 (15.7) 47 (7.5)
Grade 3Footnote b 5 (0.2) 2 (0.3) 9 (0.5) 3 (0.5)
Arthralgia
Any 124 (6.2) 32 (4.9) 168 (8.5) 28 (4.5)
Grade 3Footnote b 2 (< 0.1) 1 (0.2) 3 (0.2) 0 (0)
Nausea/vomiting
Any 137 (6.8) 50 (7.7) 194 (9.8) 30 (4.8)
Grade 3Footnote b 7 (0.3) 2 (0.3) 6 (0.3) 0 (0)
Chills
Any 129 (6.4) 40 (6.2) 245 (12.4) 31 (4.9)
Grade 3Footnote b 1 (< 0.1) 0 (0) 10 (1.0) 2 (0.6)

n= # of participants with specified reaction, percentages are based on n/N.
N= number of exposed subjects who submitted any data for the event.

Table 5 Footnote a

Placebo was a saline solution.

Table 5 Return to footnote a referrer

Table 5 Footnote b

Grade 3 headache, fatigue, myalgia, arthralgia, nausea/vomiting and chills: Defined as prevents daily activity

Table 5 Return to footnote b referrer

The information in this table is up to date as of July 14, 2022. For updated information, please consult the SPIKEVAX product monograph.

References

Footnote 1

Ismail SJ, Langley JM, Harris TM, Warshawsky BF, Desai S, FarhangMehr M. Canada's National Advisory Committee on Immunization (NACI): Evidence-based decision-making on vaccines and immunization. Vaccine. 2010;28:A58,63. doi: 10.1016/j.vaccine.2010.02.035.

Return to footnote 1 referrer

Footnote 2

Ismail SJ, Hardy K, Tunis MC, Young K, Sicard N, Quach C. A framework for the systematic consideration of ethics, equity, feasibility, and acceptability in vaccine program recommendations. Vaccine. 2020 Aug 10;38(36):5861,5876. doi: 10.1016/j.vaccine.2020.05.051.

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Footnote 3

Public Health Agency of Canada (PHAC). Surveillance and Epidemiology Division, Centre for Immunization and Respiratory Infectious Diseases, Infectious Disease Prevention and Control Branch. Data cut-off March 31, 2022. Ottawa (ON): PHAC; 2022.

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Footnote 4

Skowronski D. Personal communication. SARS-CoV-2 sero-prevalence and vaccine effectiveness (VE) update: focus on children 5-11 years, British Columbia. 2022 May 30.

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Footnote 5

COVID-19 Immunity Task Force (CITF). Personal communication. Vaccine strategies in an era of hybrid immunity. 2022 June 3.

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Footnote 6

Quach C, Renaud C, Vallières É, Desforges M. Combien d'enfants sont protégés contre la COVID-19 dans la grande région de Montréal? [Internet]. Montreal (QC): CHU Sainte-Justine; 2022 Feb 23 [cited 2022 Jun 30]. Available from: https://www.chusj.org/en/Calendrier-salle-presse/nouvelles/actualites/2022/Combien-d-enfants-sont-proteges-contre-la-COVID-19.

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Footnote 7

COVID-19 signs, symptoms and severity of disease: A clinician guide [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Jun 01 [cited 2022 Jun 30]. Available from: https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/signs-symptoms-severity.html.

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Footnote 8

Centers for Disease Control and Prevention. Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. Data cut-off May 31, 2022 [Internet]. Atlanta (GA): US Department of Health and Human Services, CDC; 2022 May 31 [cited 2022 Jun 28]. Available from: https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance.

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Footnote 9

Rapid Review: What are the risk factors associated with severe COVID-19 outcomes in children 5 years and under? [Internet]. Hamilton (ON): The National Collaborating Centre for Methods and Tools; 2022 Mar 7 [cited 2022 Jun 30]. Available from: https://www.nccmt.ca/pdfs/res/risk-factors-children-5-and-under.

Return to footnote 9 referrer

Footnote 10

Choi JH, Choi SH, Yun KW. Risk Factors for Severe COVID-19 in Children: A Systematic Review and Meta-Analysis. J Korean Med Sci. 2022 Feb 7;37(5):e35. doi: 10.3346/jkms.2022.37.e35.

Return to footnote 10 referrer

Footnote 11

Hobbs CV, Woodworth K, Young CC, Jackson AM, Newhams MM, Dapul H, et al. Frequency, Characteristics and Complications of COVID-19 in Hospitalized Infants. Pediatr Infect Dis J. 2022 Mar 1;41(3):e81,e86. doi: 10.1097/INF.0000000000003435.

Return to footnote 11 referrer

Footnote 12

Bundle N, Dave N, Pharris A, Spiteri G, Deogan C, Suk JE, et al. COVID-19 trends and severity among symptomatic children aged 0-17 years in 10 European Union countries, 3 August 2020 to 3 October 2021. Euro Surveill. 2021 Dec 16;26(50):2101098. doi: 10.2807/1560-7917.ES.2021.26.50.2101098.

Return to footnote 12 referrer

Footnote 13

Kompaniyets L, Agathis NT, Nelson JM, Preston LE, Ko JY, Belay B, et al. Underlying Medical Conditions Associated With Severe COVID-19 Illness Among Children. JAMA Netw Open. 2021 Jun 1;4(6):e2111182. doi:10.1001/jamanetworkopen.2021.11182.

Return to footnote 13 referrer

Footnote 14

van der Zalm MM, Lishman J, Verhagen LM, Redfern A, Smit L, Barday M, et al. Clinical Experience With Severe Acute Respiratory Syndrome Coronavirus 2-Related Illness in Children: Hospital Experience in Cape Town, South Africa. Clin Infect Dis. 2021 Jun 15;72(12):e938,e944. doi: 10.1093/cid/ciaa1666.

Return to footnote 14 referrer

Footnote 15

Kufa T, Jassat W, Cohen C, Tempia S, Masha M, Wolter N, et al. Epidemiology of SARS-CoV-2 infection and SARS-CoV-2 positive hospital admissions among children in South Africa. Influenza Other Respir Viruses. 2022 Jan;16(1):34,47. doi: 10.1111/irv.12916.

Return to footnote 15 referrer

Footnote 16

Woodruff RC, Campbell AP, Taylor CA, Chai SJ, Kawasaki B, Meek J, et al. Risk Factors for Severe COVID-19 in Children. Pediatrics. 2021 Dec 22:e2021053418. doi: 10.1542/peds.2021-053418.

Return to footnote 16 referrer

Footnote 17

Navarro-Olivos E, Padilla-Raygoza N, Flores-Vargas G, Gallardo-Luna MJ, León-Verdín MG, Lara-Lona E, et al. COVID-19-Associated Case Fatality Rate in Subjects Under 18 Years Old in Mexico, up to December 31, 2020. Front Pediatr. 2021 Oct 1;9:696425. doi: 10.3389/fped.2021.696425.

Return to footnote 17 referrer

Footnote 18

2.5 Clinical Overview [Moderna Pediatrics 6 months to < 6 years]. [Unpublished]. ModernaTX, Inc.; 2022.

Return to footnote 18 referrer

Footnote 19

Iqbal S. Pediatric Data Summary for mRNA-1273 [unpublished slides presented at National Advisory Committee on Immunization (NACI) meeting June 6, 2022] [Internet]. Ottawa (ON): National Advisory Committee on Immunization (NACI); 2022 Jun 06 [cited 2022 Jul 06].

Return to footnote 19 referrer

Footnote 20

Product Monograph Including Patient Medication Information: Spikevax [Internet]. Cambridge (MA): ModernaTX, Inc.; 2022 Jun 28 [cited 2022 Jul 08]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html.

Return to footnote 20 referrer

Footnote 21

mRNA-1273-P204 EUA 2 to <6 years (Data cutoff date: 21FEB2022). [Unpublished]. Cambridge (MA): ModernaTx, Inc.; 2022. Table 14.2.8.4.1.2.1 Analysis of Incidence Rate of CDC Case Definition of COVID-19* Starting After First Injection by Age Group and Time Period mITT1 Set; p. 435-445.

Return to footnote 21 referrer

Footnote 22

mRNA-1273-P204 EUA 6 months to <2 years (Data cutoff date: 21FEB2022). [Unpublished]. Cambridge (MA): ModernaTx, Inc.; 2022. Table 14.2.8.4.1.2.1 Analysis of Incidence Rate of CDC Case Definition of COVID-19* Starting After First Injection by Age Group and Time Period mITT1 Set; p. 266- 276.

Return to footnote 22 referrer

Footnote 23

Oliver S. mRNA COVID-19 vaccines in young children: Summary and Work Group interpretation [slides presented at Advisory Committee on Immunization Practices (ACIP) meeting June 17, 2022] [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2022 Jun 17 [cited 2022 Jun 30]. Available from: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-06-17-18/06-COVID-Oliver-508.pdf.

Return to footnote 23 referrer

Footnote 24

Zambrano LD, Newhams MM, Olson SM, Halasa NB, Price AM, Boom JA, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021. MMWR Morb Mortal Wkly Rep. 2022 Jan 14;71(2):52,58. doi: 10.15585/mmwr.mm7102e1.

Return to footnote 24 referrer

Footnote 25

Fowlkes AL, Yoon SK, Lutrick K, Gwynn L, Burns J, Grant L, et al. Effectiveness of 2-Dose BNT162b2 (Pfizer BioNTech) mRNA Vaccine in Preventing SARS-CoV-2 Infection Among Children Aged 5-11 Years and Adolescents Aged 12-15 Years - PROTECT Cohort, July 2021-February 2022. MMWR Morb Mortal Wkly Rep. 2022 Mar 18;71(11):422,428. doi: 10.15585/mmwr.mm7111e1.

Return to footnote 25 referrer

Footnote 26

Moderna. Personal Communication. 2022 Jun 21.

Return to footnote 26 referrer

Footnote 27

Nilsson L, Csuth Á, Storsaeter J, Garvey LH, Jenmalm MC. Vaccine allergy: evidence to consider for COVID-19 vaccines. Curr Opin Allergy Clin Immunol. 2021 Aug 1;21(4):401,409. doi: 10.1097/ACI.0000000000000762.

Return to footnote 27 referrer

Footnote 28

Immunocompromised persons: Considerations. In COVID-19 vaccine: Canadian Immunization Guide [Internet]. Ottawa (ON): Public Health Agency of Canada; 2022 Jun 29 [cited 2022 Jul 04]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-26-covid-19-vaccine.html#a6.4.considerations.

Return to footnote 28 referrer

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