Effectiveness of mRNA-1273, BNT162b2, and BBIBP-CorV vaccines against infection and mortality in children in Argentina, during predominance of delta and omicron covid-19 variants: test negative, case-control study - The BMJ

Objective To estimate the effectiveness of a two dose vaccine schedule (mRNA-1273, BNT162b2, and BBIBP-CorV) against SARS-CoV-2 infection and covid-19 related death and short term waning of immunity in children (3-11 years old) and adolescents (12-17 years old) during periods of delta and omicron variant predominance in Argentina.

Participants 844 460 children and adolescents without previous SARS-CoV-2 infection eligible to receive primary vaccination schedule who were tested for SARS-CoV-2 by polymerase chain reaction or rapid antigen test from September 2021 to April 2022.

Results Estimated vaccine effectiveness against SARS-CoV-2 infection was 61.2% (95% confidence interval 56.4% to 65.5%) in children and 66.8% (63.9% to 69.5%) in adolescents during the delta dominant period and 15.9% (13.2% to 18.6%) and 26.0% (23.2% to 28.8%), respectively, when omicron was dominant.

Vaccine effectiveness declined over time, especially during the omicron period, from 37.6% (34.2% to 40.8%) at 15-30 days after vaccination to 2.0% (1.8% to 5.6%) after ≥60 days in children and from 55.8% (52.4% to 59.0%) to 12.4% (8.6% to 16.1%) in adolescents.

Vaccine effectiveness against death related to SARS-CoV-2 infection during omicron predominance was 66.9% (6.4% to 89.8%) in children and 97.6% (81.0% to 99.7%) in adolescents.

Conclusions Vaccine effectiveness in preventing mortality remained high in children and adolescents regardless of the circulating variant.

Vaccine effectiveness in preventing SARS-CoV-2 infection in the short term after vaccination was lower during omicron predominance and decreasing sharply over time.

Although a systematic review found that low-middle income countries may have larger proportion of paediatric fatality due to covid-19 than high income countries,10 evidence on the effectiveness of vaccination, especially to prevent mortality in children and adolescents, is scarce.11121314 Some studies evaluated vaccine effectiveness for inactivated vaccines, but only one included BBIBP-CorV and only two reported effectiveness in preventing infection in children under 5 years old.15161718 The study that evaluated BBIBP-CorV vaccine effectiveness in children was conducted in Buenos Aires Province (Argentina) and estimated that vaccine effectiveness in preventing hospital admission in 3-11 year old children was 76.4% (95% confidence interval 62.9% to 84.5%).

However, this study did not evaluate effectiveness for preventing infection or mortality or loss of effectiveness over time.17.

Moreover, although several studies reported a decline in effectiveness over time with the BNT162b2 vaccine in children or adolescents, scarce evidence exists of changes in effectiveness with inactivated vaccines or of differences related to SARS-CoV-2 variants.

Therefore, the aim of this study was to evaluate the effectiveness of two dose schedules of mRNA-1273, BNT162b2, and BBIBP-CorV vaccines in preventing SARS-CoV-2 infection and death related to covid-19 in children and adolescents, aged 3-17 years, during periods of delta and omicron BA.1 predominance between September 2021 and April 2022 in Argentina.

Additionally, we aimed to assess the effect of the diagnostic method used for estimating vaccine effectiveness, the effectiveness of different combinations of mRNA vaccines, and short term waning of immunity in children and adolescents.

We considered 12-17 year old adolescents to be fully vaccinated if they had received two doses of a homologous or heterologous schedule with BNT162b2 and/or mRNA-1273 and had received the second dose a minimum of 14 days before testing.

Finally, for a fatality analysis, we matched participants with covid-19 associated death one to four to covid-19 negative participants by using the same matching criteria as the one used in the primary analysis estimating vaccine effectiveness against SARS-CoV-2 infection.

Vaccination schedule and vaccine effectiveness against infection, by combination and period.

Figure 3 shows vaccine effectiveness in preventing infection according to the predominant variant and age group.

Vaccine effectiveness was considerably higher in all age groups when we analysed only the period of delta variant predominance.

Vaccine effectiveness was 64.2% (95% confidence interval 61.6% to 66.5%) for all ages, 61.2% (56.4% to 65.5%) for children (3-11 years), and 66.8% (63.9% to 69.5%) for adolescents (12-17 years).

Vaccine effectiveness was 19.9% (18.0% to 21.8%) for all ages, with a slightly higher value in adolescents who received mRNA based vaccines (26.0%, 23.2% to 28.8%) than in children who received BBIBP-CorV (15.9%, 13.2% to 18.6%).

Vaccine effectiveness of two dose schedules against SARS-CoV-2 infection, by age group and study period.

As shown in figure 4, during the delta period, vaccine effectiveness declined according to time since vaccination from 68.4% (64.1% to 72.2%) at 15-30 days to 65.2% (44.0% to 78.4%) at ≥61 days in children and from 74.8% (71.3% to 77.9%) to 56.3% (50.2% to 61.7%) in adolescents (supplementary table E).

Vaccine effectiveness (with 95% confidence interval) of two dose schemes against SARS-CoV-2 infection, by age group, study period, and days since second dose.

During the delta period, vaccine effectiveness was 70.2% (66.8% to 73.1%) for the homologous schedule of mRNA-1273 and 64.1% (60.5% to 67.3%) for BNT162b2.

The heterologous schedule of mRNA-1273 then BNT162b2 yielded a vaccine effectiveness of 66.3% (54.0% to 75.4%), and that for BNT162b2 then mRNA-1273 was 88.9% (66.1% to 96.4%).

In the omicron period, homologous schedules of mRNA-1273 and BNT162b2 showed a vaccine effectiveness of 17.9% (14.0% to 21.5%) and 28.1% (25.2% to 30.8%), respectively.

After adjusting a conditional logistic regression model, we found that vaccine effectiveness against mortality in the 3-17 year old group for the two dose schedule was 89.3% (73.9% to 95.6%).

Considering age subgroups, vaccine effectiveness against death related to SARS-CoV-2 infection during omicron predominance was 97.6% (81.0% to 99.7%) for adolescents and 66.9% (6.4% to 89.8%) for children.

This study provides real world evidence for the effectiveness of mRNA-1273, BNT162b2, and BBIBP-CorV vaccines in preventing infection and mortality in children and adolescents in Argentina.

To our knowledge, this is one of the first studies that reports vaccine effectiveness in children under 5 years old, in addition to evaluation of mortality and analysis of waning for BBIP-CoV and mRNA-1273 vaccines.

Our results suggest that the primary vaccination schedule is effective in preventing mortality in children and adolescents with covid-19 regardless of the circulating SARS-CoV-2 variant.

Vaccine effectiveness in preventing mortality in children vaccinated with BBIP-CoV was lower than in adolescents vaccinated with mRNA vaccines; however, owing to the scarcity of events, analysis of mortality by age group yielded results with wide confidence intervals.

Our estimates also suggest that two doses of vaccine are effective in preventing SARS-CoV-2 infection in children and adolescents in the short term.

Nevertheless, BNT162b2 vaccine effectiveness in preventing infection during omicron predominance has been evaluated, with vaccine effectiveness between 29.4% and 51% being reported.122324 These results are similar to the vaccine effectiveness reported in our study and in other studies that evaluated inactivated vaccines (CoranaVac) and reported vaccine effectiveness of 39.8% and 38.2%.1618.

In addition, our results are consistent with other published studies that found high short term protection induced by the primary vaccination regimen against SARS-CoV-2 infection during the delta predominance period.262728 However, since the emergence and spread of the omicron variant of concern, a reduction in vaccine effectiveness in preventing infection has been observed in adults and children.13293031 A population based study in Norway reported that one and two doses of mRNA vaccine (BNT162b2) in adolescents protected against infection with the delta variant, reaching an effectiveness of 91% after the primary vaccination schedule and declining to 53% for the omicron variant.28 Fowlkes and colleagues described a decrease in vaccine effectiveness against infection in adolescents for the primary mRNA vaccine series (BNT162b2) from 87% to 59%, comparing delta and omicron variants.12 In Chile, Jara and colleagues reported vaccine effectiveness in preventing infection for a complete schedule of inactivated vaccine (Sinovac’s CoronaVac) in 6-11 year old children of 75.8% during the delta circulating period.

In another study, Jara and colleagues reported a lower vaccine effectiveness of 38.2% during omicron circulation for the same vaccine in 3-5 year old children.1516 Vaccine effectiveness reported by Jara and colleagues is similar to that observed with BBIBP-CorV in children in our study.

Available evidence suggests that the vaccine induced immune response could decrease over time, with a reduction in the effectiveness of SARS-CoV-2 vaccines in preventing infection, particularly in the context of the emergence of new variants of the virus with potential ability to partially evade the host immune response.3233 Our results highlight not only a decrease in effectiveness when comparing delta with omicron but also, and especially during omicron predominance, a significant decrease with time since vaccination.

Fleming-Dutra and colleagues did a test negative, case-control analysis to evaluate the vaccine effectiveness of BNT162b2 in preventing infection among children and adolescents during omicron variant predominance and reported that two months after the second dose the estimated vaccine effectiveness had declined in both age groups.34 Similarly, Dorabawila and colleagues concluded that the risk of infection and hospital admission was higher in unvaccinated children and adolescents, although the protection declined over time from vaccination.30 Sacco and colleagues reported a decrease in vaccine effectiveness for BNT162b2 in preventing infection over time, and Klein and colleagues found no evidence of protection for adolescents aged 12-17 years after receipt of two doses of BNT162b2 ≥150 days earlier during omicron predominance.2329 In a Norwegian study, protection against omicron after a complete primary regimen in adolescents was reduced to 23% from 63 days post-vaccination, whereas a smaller reduction was documented for delta.28 Amir and colleagues observed a rapid reduction in protection against omicron of two doses of mRNA vaccine (BNT162b2) in adolescents aged 12-15, with an increase in the rate of confirmed infections from 60 days after the second dose.35 Evidence of a decrease in vaccine effectiveness after inactivated vaccines is lacking.

Although the previously cited studies suggest a reduction in vaccine effectiveness for SARS-Cov-2 infection over time, observational studies have shown that vaccine effectiveness against severe disease is higher and more stable.

Data from Brazil and Scotland in adolescents aged 12-17 years during the omicron wave showed a reduction in BNT162b2 vaccine effectiveness for symptomatic infection from 98 days after receipt of the primary schedule.

However, protection against hospital admission and death with covid-19 remained above 80% in the same time interval.36 In Canada, vaccine effectiveness for two doses of BNT162b2 against severe disease with omicron in the same age group was 85%, with a stable trend over time.37 In children, Tan and colleagues reported a vaccine effectiveness of 82.7% in preventing hospital admission for BNT162b2.38 For inactivated vaccines, vaccine effectiveness of 59.2% and 64.6% have been reported for prevention of hospital admission with Sinovac’s CoronaVac.1618.

Our results are consistent with a study conducted in Buenos Aires Province (Argentina) that reported a two dose vaccine effectiveness of 78.0% for hospital admission in 3-17 year olds evaluated during delta/omicron circulation.17 As expected, we found that vaccine effectiveness for infection was lower and vaccine effectiveness for mortality was higher than these estimations for protection against hospital admissions, especially in adolescents.

However, it did not evaluate vaccine effectiveness in preventing infection or mortality or decrease in vaccine effectiveness over time.17.

Our study evaluated vaccine effectiveness in children and adolescents, including different types of diagnostic tests.

Firstly, the sample size was large and included all children and adolescents tested and reported to the National Surveillance System in Argentina during the study period.

Vaccine effectiveness remained high for preventing mortality in children and adolescents regardless of the predominant circulating variant.

mRNA and inactivated covid-19 vaccines are effective in preventing severe disease and infection in children and adolescents in the short term after vaccination, but data on mortality are lacking.

Vaccine effectiveness remained high for preventing mortality in children and adolescents aged 3-17 years, regardless of the predominant circulating variant.