The fifth wave of Coronavirus disease 2019 (COVID-19) has caused more than a million people being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Omicron BA.2, predominant) and over 9,000 COVID-19-associated deaths in Hong Kong.¹ Children, a subgroup of the population who had experienced more favorable outcomes vs. the older adults during the first 4 waves of the pandemic, were reported to have disproportionately higher hospitalization rates under the Omicron era.² Some studies revealed that seizure and laryngotracheobronchitis, or croup, were common severe complications which led to pediatric hospitalization.² The findings highlighted the importance of COVID-19 vaccination among children, but those aged <5 years were still not eligible for this mitigation measure. In an interview with Omnihealth Practice, Dr. Leung, Sze-Yin Agnes presented the latest safety and efficacy data of BNT162b2 among children aged ≥6 months and encouraged parents to arrange COVID-19 vaccination for their children to reduce the negative impact of this pandemic in young children.  

The need for COVID-19 vaccination in children aged <5 years

Since the emergence of the Omicron variant, the COVID-19-related hospitalization rates have surged significantly around the world among children aged <5 years, a group not yet eligible for COVID-19 vaccination before June 2022 (note: CZ02 is recommended for children aged ≥3 years in Hong Kong).^3,4  In the United States (US), the weekly COVID-19-associated hospitalization rates during the Omicron-predominant period peak (i.e., from December 2021 to February 2022) were reported to be 14.5/100,000 children aged <5 years, approximately 5 times during the period of Delta predominance (RR=5.0; 95% CI: 3.8-6.8).³ Similarly, the intensive care unit (ICU) admission rates were also higher during Omicron vs. Delta predominance (i.e., 3.5 times higher).³ Of note, about 63% of hospitalized infants and children infected with Omicron had no underlying medical conditions, implying that the occurrence of severe complications from Omicron infection can be unpredictable.³ In Prince of Wales Hospital (PWH), a total of 422 children infected with SARS-CoV-2 were admitted between December 21, 2021, and April 22, 2022 (i.e. period of Omicron predominance).⁵ Among them, 65% of the hospitalized children were aged <5 years, echoing the above US data that children, particularly the young ones, are susceptible to COVID-19 infection during the Omicron era.^3,5

Some studies suggested that Omicron BA.2 appeared to be more pathogenic in the upper airway and the central nervous system (CNS) than influenza virus.² A local study from the University of Hong Kong, which included 1,144 hospitalized children aged <12 years (80.2% were aged <5 years) and previously uninfected and unvaccinated during the Omicron wave, found that the risks for neurological complications (Adjusted RR=1.6; 95% CI: 1.4-1.9; p<0.001) and croup (Adjusted RR=2.0; 95% CI: 1.5-2.6; p<0.001) appeared to be higher with Omicron vs. influenza virus.² Given the seemingly higher risk of Omicron vs. influenza infection for which children are routinely vaccinated, a similar approach of COVID-19 vaccination should be adopted to protect children against serious COVID-19-associated complications and death.

Demonstrated safety, immunogenicity, and efficacy of BNT162b2 in children aged 6 months to <5 years

BNT162b2, the messenger ribonucleic acid (mRNA) vaccine adopted for COVID-19 vaccination for people aged >5 years in Hong Kong, was evaluated in a phase 2/3 randomized controlled trial for the safety, immunogenicity, and efficacy among children aged between 6 months and 5 years.^4,6 A total of 4,526 eligible children with or without prior SARS-CoV-2 infection were enrolled and randomized 2:1 to receive 3 doses of either 3µg (1/10 of adult dose) of BNT162b2 and placebo, according to the prespecified schedule (figure 1).⁶ The immune response among BNT162b2 children aged 6 months to <5 years were assessed and were found to be non-inferior to adults aged 18 to 25 years in whom the clinical efficacy of BNT162b2 had been established, with the geometric mean titer ratios (GMRs) of 1.19 (95% CI: 1.00-1.42) and 1.30 (95% CI: 1.13-1.50) for children aged 6-23 months and 2-4 years, respectively.⁶ In addition, a high vaccine efficacy of 80.3% (95% CI: 13.9-96.7) against symptomatic disease from 3 doses of BNT162b2 among children aged 6 months and <5 years was achieved (figure 2).⁶ Notably, consistent with adult data, 2 doses of BNT162b2 was found to be insufficient to neutralize the Omicron variant (figure 2).⁶

Overall, this trial has shown that 3 doses of BNT162b2 were well tolerated among children aged 6 months and <5 years.⁶ The reported local and systemic reactions with BNT162b2 were mostly mild to moderate, which were similar to placebo.⁶ Fatigue was the most reported systemic adverse event (AE) among the vaccinees, and serious AEs were extremely rare (figure 2).⁶ During the study period, no vaccine-related anaphylaxis, myocarditis, Bell’s palsy, or multisystem inflammatory syndrome in children (MIS-C) were reported.⁶

VE of BNT162b2 among children aged 5-17 years against Omicron

A recent case-control analysis (n=121,952) found that the VE of BNT162b2 among children aged 5-11 years and adolescents aged 12-15 was reduced and waned rapidly during the Omicron predominance, decreasing from 60.1% (95% CI: 54.7-64.8%; for children) and 59.5% (95% CI: 44.3-70.6%; for adolescents) 2-4 weeks after dose 2 to 28.9% (95% CI: 24.5-33.1%) and 16.6% (95% CI: 8.1-24.3%) during month 2 post dose 2, respectively.⁷ Adolescents were given a booster, and the VE was increased to 71.1% (95% CI: 65.5-75.5%) 2-6.5 weeks after dose 3 (Note: BNT162b2 booster was not indicated for children aged below 12 during this study).⁷ These results revealed the waning protection against Omicron with 2 doses of BNT162b2 over time among children aged 5-17 years, and a 3^rd dose might be required.

Currently in Hong Kong, the Scientific Committees joined by the Chief Executive’s Expert Advisory Panel (JSC-EAP) recommend 2 doses of BNT162b2 for children aged 5-11 years at least 8 weeks apart and 3 doses for children aged 12-17 years with the first 2 doses 8 weeks apart and a 3^rd dose at least 5 months later to protect children from severe COVID-19-associated complications and death.⁴

MIS-C and VE of BNT162b2

MIS-C is a severe post-infectious hyperinflammatory condition with features resembling Kawasaki Disease, toxic shock syndrome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome.^8-10 The clinical manifestations of MIS-C include fever and severe illnesses involving ≥2 organ systems, together with abnormal laboratory findings in inflammatory biomarkers (figure 3).⁹ MIS-C has been first reported in late April 2020 and generally occurs 2-6 weeks after a mild or asymptomatic infection with SARS-CoV-2 among children.⁸ Since MIS-C is a serious complication of COVID-19 among children and can be life-threatening, preventive measures are warranted.

The VE of BNT162b2 in preventing MIS-C and severe complications from MIS-C among children aged 12-18 years was evaluated in a test-negative case-control study in the US.⁸ A total of 102 MIS-C patients case-patients and 181 hospitalized controls were selected from approximately 70 pediatric hospitals.⁸ Among the 102 MIS-C patients, 97 (95%) were unvaccinated and 5 (5%) had received 2 doses of BNT162b2, yielding a VE of  91% (95% CI: 78%-97%) with 2 doses of BNT162b2 in preventing MIS-C.⁸ Moreover, 38 MIS-C patients became critically ill and required life support during hospitalization.⁸ Of note, all patients who had received life-saving measures were unvaccinated.⁸ The results showed that 2 doses of BNT162b2 were highly effective against MIS-C in children aged 12-18 years, reinforcing the COVID-19 recommendation for eligible children.

T-cell immune response of BNT162b2

Since the introduction of BNT162b2, waning antibody titers and multiple reports of breakthrough infection have raised public concerns over the VE durability.¹¹ However, as BNT162b2 can induce both humoral and cell-mediated immune responses against spike proteins of SARS-CoV-2, the spike-specific T-cell response of BNT162b2 should also be taken into account when evaluating the duration of protection.¹¹ Over the past 2 years, several studies have been conducted to evaluate BNT162b2-induced T-cell responses.¹¹

One of the studies revealed that a high level of T-cell response was achieved with 3 doses of BNT162b2.¹² While the T-cell response, defined as the frequency of tissue necrosis factor (TNF)-producing CD4+ T-cells and interleukin-2 (IL-2)-producing CD4+ T-cells against the Omicron spike protein, with 2 doses of BNT162b2 was reduced by the spike mutations of Omicron, 3 doses of BNT162b2 were shown to have elicited a high level of T-cell response against the Omicron variant which was comparable to that achieved by 2 doses of BNT162b2 against the wild-type spike protein.¹² These findings further supported the 3-dose BNT162b2 vaccination among eligible people.

Long-term safety is not a concern for mRNA vaccines

Since the 1990s, mRNA has been deemed an ideal vaccine platform due to its immunological features, such as endogenous antigen expression and T-cell induction, which are similar to that from live attenuated vaccines.¹³ However, molecular instability, rather than safety, of mRNA had been the biggest obstacle that hindered the development of this promising vaccine platform.¹³ With advances in in vitro transfection techniques, scientists eventually managed to stabilize and deliver the mRNA molecules to human cells for protein expression.¹³

As for safety, mRNA-based vaccines in fact offer strong safety advantages, particularly when compared with DNA vaccines.¹³ Specifically, mRNA molecules are only minimal and transient carriers of information that have no interaction with the genome.¹² Furthermore, mRNA molecules do not self-replicate inside human body, and will decay and be metabolized within a few days after administration. In other words, the likelihood of potentially detrimental genomic integration which could lead to carcinogenesis is excluded, and long-term safety concerns for unexpected malignancies do not exist.¹³

Conclusion

The 5^th wave of COVID-19 outbreak in Hong Kong has indicated that our population, including children aged 6 months to 17 years, was susceptible to the highly contagious and pathogenic Omicron. In addition,  the VE of BNT162b2 also became lower against Omicron vs. ancestral variants. Fortunately, compelling data has demonstrated that 3-dose BNT162b2 vaccination can still confer strong protection against severe COVID-19 disease and death among children and adolescents aged above 6 months, and thus it should be recommended for all eligible individuals, particularly in the course of gradual transition to living with COVID-19. “We will never know how severe the disease will be when our children contract Omicron; it’s wiser not to risk our children’s lives and act now,” concluded Dr. Leung.