Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study

Abstract

Objective To estimate the effectiveness of the bivalent mRNA booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 or BA.1 subvariants as the fourth dose against severe covid-19. Design Nationwide cohort analyses, using target trial emulation. Setting Denmark, Finland, Norway, and Sweden, from 1 July 2022 to 10 April 2023. Participants People aged ≥50 years who had received at least three doses of covid-19 vaccine (that is, a primary course and a first booster). Main outcome measures The Kaplan-Meier estimator was used to compare the risk of hospital admission and death related to covid-19 in people who received a bivalent Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) BA.4-5 or BA.1 mRNA booster vaccine as a fourth dose (second booster) with three dose (first booster) vaccinated people and between four dose vaccinated people. Results A total of 1 634 199 people receiving bivalent BA.4-5 fourth dose booster and 1 042 124 receiving bivalent BA.1 fourth dose booster across the four Nordic countries were included. Receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a comparative vaccine effectiveness against admission to hospital with covid-19 of 67.8% (95% confidence interval 63.1% to 72.5%) and a risk difference of –91.9 (95% confidence interval –152.4 to –31.4) per 100 000 people at three months of follow-up compared with having received three doses of vaccine (289 v 893 events). The corresponding comparative vaccine effectiveness and risk difference for bivalent BA.1 boosters (332 v 977 events) were 65.8% (59.1% to 72.4%) and –112.9 (–179.6 to –46.2) per 100 000, respectively. Comparative vaccine effectiveness and risk difference against covid-19 related death were 69.8% (52.8% to 86.8%) and –34.1 (–40.1 to –28.2) per 100 000 for bivalent BA.4-5 booster (93 v 325 events) and 70.0% (50.3% to 89.7%) and –38.7 (–65.4 to –12.0) per 100 000 for BA.1 booster (86 v 286) as a fourth dose. Comparing bivalent BA.4-5 and BA.1 boosters as a fourth dose directly resulted in a three month comparative vaccine effectiveness and corresponding risk difference of –14.9% (–62.3% to 32.4%) and 10.0 (–14.4 to 34.4) per 100 000 people for admission to hospital with covid-19 (802 v 932 unweighted events) and –40.7% (–123.4% to 42.1%) and 8.1 (–3.3 to 19.4) per 100 000 for covid-19 related death (229 v 243 unweighted events). The comparative vaccine effectiveness did not differ across sex and age (</≥70 years) and seemed to be sustained up to six months from the day of vaccination with modest waning. Conclusion Vaccination with bivalent BA.4-5 or BA.1 mRNA booster vaccines as a fourth dose was associated with reduced rates of covid-19 related hospital admission and death among adults aged ≥50 years. The protection afforded by the bivalent BA.4-5 and BA.1 boosters did not differ significantly when directly compared, and any potential difference would most likely be very small in absolute numbers.

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters

“…Based on this assumption, variant-modified booster vaccinations were predicted to offer an elevated level of protection 28 . While the overall effectiveness of Omicron bivalent vaccination has been described 23 , 29 – 31 , we show that the cross-neutralization of the BA.2-descendent Omicron variant XBB.1.5, which was circulating at the time of the study, was poor after administration of either the Omicron BA.1 or the BA.5 bivalent booster vaccine, in line with previous reports 4 – 6 . Interestingly, this relative reduction of XBB.1.5 neutralizing antibodies compared to the level of neutralizing antibodies against ancestral SARS-CoV-2 or Omicron BA.1/BA.5 was not reflected by the binding antibody levels towards the XBB.1.5 S protein, which was comparable to BA.1/BA.5-binding antibody levels.…”

Predicting COVID-19 booster immunogenicity against future SARS-CoV-2 variants and the benefits of vaccine updates

“…Effectiveness of the BA.4/5 booster against symptomatic disease has been shown to have similar benefit compared to an ancestral booster (additional protection of BA.5 vaccine compared to an Ancestral vaccine was estimated at 8%, [95% CI 0-16%]) 45 . In a comparison between boosters containing the BA.1 and BA.5 immunogens, little difference was discernible 46 . Thus, although there are fewer comparisons available, the data on clinical protection support the idea that updated boosters may provide a small increase in clinical protection; however, better prospective data collection on the effectiveness of different booster regiments would add valuable information.…”

Bivalent COVID-19 vaccines boost the capacity of pre-existing SARS-CoV-2-specific memory B cells to cross-recognize Omicron subvariants

“…Bivalent vaccines proved significantly more effective at preventing infection and particularly severe disease or death from Omicron variants compared to monovalent WH1 vaccines ( 11–13 ). Bivalent boosters elicited equivalent levels of NAb against WH1 compared to monovalent vaccines, and increased NAb levels against the Omicron subvariant encoded by the bivalent vaccine, as well as descendant subvariants ( 14–17 ).…”