A recent study published in the Open Forum Infectious Diseases journal evaluated the impact of the lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine dosages in younger populations.
In most age groups, the SARS-CoV-2 messenger ribonucleic acid RNA (mRNA) vaccinations were significantly successful in protecting against the CoV disease 2019 (COVID-19) pandemic. According to the most recent data, vaccine efficacy (VE) of SARS-CoV-2 mRNA vaccines appears to be lower in children aged five to 11 than in adults. Besides, understanding the reason for this phenomenon is essential for creating appropriate vaccination approaches for this population moving forward.
The present work analyzed the VE of COVID-19 mRNA vaccines and the associated mechanisms in adolescents, children, and young adults, given the vaccine doses were lower in these groups compared to adults.
COVID-19 mRNA vaccine efficacy in young adults, children, and adolescents
VE of the SARS-CoV-2 BNT162b2 vaccine in five- to 11-year-olds against COVID-19 was 91% during the two-month monitoring period in a clinical experiment before the emergence of the Omicron variant in the United States (US). Following the vaccine's approval on October 29, 2021, children were fully vaccinated by December 13, 2021, just in time with the introduction of Omicron.
However, according to preliminary information from the New York State Department of Health, VE in children aged 5 to 11 decreased from 68 to 12%, and hospitalization rates from 100 to 48% during December 13, 2021, compared to January 24, 2022. On the other hand, VE in those aged 12 to 17 dropped from 66 to 51% for infections and from 85 to 73% for hospitalization.
During the study period, Omicron infections in New York increased from 19% on December 13, 2021, to above 99% on January 24, 2022. The median period following vaccination was 51 days for children aged 5 to 11 and 211 days for those aged 12 to 17.
When removing the confounding effect of time after vaccination from an examination of recently vaccinated children from New York, the incidence rate ratio for infection was 1.1 for those aged five to 11 and 2.3 for 12 to 17 years at 28 to 34 days after immunization. When the analysis was limited to the Omicron period, information from the Centers for Disease Control and Prevention (CDC) demonstrated slight variation by age, with a VE of 51% in children aged 5 to 11, compared to 45% and 34%t in children aged 12 to 15 and 16 to 17, respectively.
However, during the pooled Delta- and Omicron-predominant timeframes, two-dose VE towards COVID-19-linked hospitalization for five–11, 12–15, and 16–17 years continued at 73 to 94%. The available results indicate that BNT162b2 was less effective in younger children, yet further research is required to corroborate these findings.
Mechanisms of reduced vaccine efficacy in younger age groups
One theory holds that the lower dosage of 10 µg of BNT162b2 delivered three weeks apart was the cause of the poor efficacy in children aged 5 to 11; however, evidence on neutralizing antibodies suggests that this was not the case. The evidence presented at the Vaccines and Related Biological Products Advisory Committee meeting on October 26, 2021; Advisory Committee on Immunization Practices (ACIP) meeting on November 2, 2021; and Food and Drug Administration (FDA) and CDC Advisory Committee meetings posit that adolescents, children, and young adults might attain an optimum humoral reaction with the existing BNT162b2 vaccine doses.
Two 30-µg BNT162b2 doses administered in a 21-day interval resulted in geometric mean 50% neutralization titers of SARS-CoV-2 of 1146.5 and 1239.5 in individuals aged 16 to 25 and 12 to 15 years, respectively, one month after the second shot. Almost identical titers, 1197.6, were attained in children aged 5 to 11 years after two 10-µg doses administered three weeks apart.
Children aged 9-11, 7-8, and 5-6 years acquired almost identical titers of 1191.5, 1236.1, and 1164.1 when further analyzed by age subgroup. These titers show that children and young adults have significant humoral immune reactions because they were more than three times higher than the peak titers attained by adults seven days following the second dose. As a result, it was conceivable that doses below 10 µg could still produce significant levels of neutralizing antibodies in five to 11-year-old children.
Other causes for the decreased VE must be considered because, with the current dose, adolescents, children, and young adults produce noticeably high titers than adults. The Omicron variant reduces the efficacy of the COVID-19 vaccinations in all populations, which most likely explains a large portion of the decreased efficacy among children aged 5 to 11 years. Other possible explanations include the younger cohort's shorter time between vaccination and infection, variations in circulating viral strains among age cohorts, past SARS-CoV-2 exposure, and unidentified lower effectiveness of mRNA vaccines among younger populations.
After vaccination, T- and B-cell responses continue to develop for several months, as does immunity against severe illness. Therefore, the 51-day post-vaccination period for children aged 5 to 11 compared to 211 days for children aged 12 to 17 in New York might have attributed to the lower efficacy against hospitalization seen in the younger sample.
Furthermore, given the dramatic rise in Omicron occurrence over the study period, there might have been variations in the variants circulating in high, elementary, and middle schools. Besides, there was a significant SARS-CoV-2 seroprevalence in the US. Before the Delta variant increase, the age group of five to 11 had the highest seroprevalence in June 2021 at 42%. Previous SARS-CoV-2 exposure was linked to a decreased risk of catastrophic outcomes, but it was unclear how this may have changed the population's immune reactions.
Approaches to enhance VE in younger age groups
The team noted that mRNA vaccination was a novel vaccination approach that induces both T- and B-cell responses and shows promise for producing superior vaccines against numerous pathogens, some of which are now under development. Yet, an initial trial of the two-dose BNT162b2 series found the approach was ineffective in children aged two to five. Thus, the experiment was changed to assess a three-dose series.
Factors like prior seasonal CoV exposure might have a part in the notably altered immunological response seen in older people that were not present in younger children not exposed to CoVs as much or at all. Maximizing CoV vaccination in children depends on understanding the mechanism causing BNT162b2's decreased efficacy in children.
Altering the dose intervals was one action tried to enhance immunogenicity in individuals between the ages of 12 and 39. New research has shown that spreading out the initial and second doses of mRNA vaccines increases immunogenicity while reducing adverse reactions.
On February 4, 2022, the ACIP reviewed the new information regarding extended dose intervals and published a recommendation that an eight-week gap could be ideal for some individuals aged 12 and older, particularly for males between the ages of 12 to 39. The ongoing clinical trial for BNT162b2 has been expanded to include formal evaluation of the lower 10-µg dose, administered in two doses eight weeks apart for patients aged 12 to 18 and older. The team highlighted the need for studies examining longer dosing gaps in children under 12 years to see if this tactic can increase the immunogenicity and effectiveness of mRNA vaccines in younger populations.
Side effects of present mRNA vaccines doses in younger cohorts
With the present dose of the mRNA vaccines, adolescents, children, and young adults also face higher side effects in addition to reduced efficacy. The cause of COVID-19 vaccine-associated myocarditis was unknown. However, the prevalence of this uncommon event was lower after vaccination with BNT162b2 (30 µg per dose) than mRNA-1273 (100 µg per dose), reinforcing the idea that the myocarditis may be dose-related.
COVID-19 vaccine-related myocarditis was also more frequent after the second shot, especially with dosing intervals of ≤ four weeks. However, increasing the time between the first and second doses to eight weeks reduced the frequency of myocarditis.
The FDA Brief for October 26, 2021, meeting noted that COVID-19 vaccine-linked myocarditis was probably related to dose number and dosage. Nevertheless, the decreased myocarditis incidence after the third or booster shot relative to the reduced incidence with extended dosing intervals, implies that interval spacing, instead of dose number, might be the strategy to minimize myocarditis.
According to the study findings, the SARS-CoV-2 mRNA vaccinations demonstrated reduced efficacy in children aged 5 to 11. Neutralizing antibody titers induced by the COVID-19 vaccines in adolescents, children, and young adults illustrated that lower dosage was not responsible for the lower VE in these cohorts.
Optimizing COVID-19 vaccination approaches for younger populations in the future requires figuring out whether mRNA vaccination techniques were less effective in younger cohorts and identifying if adolescents, children, and young adults need adjusting the dosage, dosing gaps, and the number of doses.