Bivalent COVID Shots May Hold Up Better Against Severe Omicron

A second booster with an mRNA bivalent vaccine offered the best protection against severe COVID-19 due to the Omicron BA.5 variant in older adults, and protection appeared to wane less than with the monovalent shot, a large retrospective study out of Italy showed.

Among over 2 million people ages 60 and up, the relative vaccine effectiveness (rVE) was 50.6% in the overall time interval 14 to 118 days post-administration for those who received a bivalent BA.4/5 booster, 49.3% with the bivalent BA.1 booster, and 26.9% with the monovalent booster, reported Alberto Mateo-Urdiales, PhD, of the Istituto Superiore di Sanità in Rome, and colleagues.

Waning of protection following the second booster dose was observed at 60 to 118 days, which was more apparent with the monovalent vaccine (rVE 20.7%) compared with the bivalent BA.1-containing vaccine (42.5%) and the BA.4/5-containing vaccine (34.7%), they noted in Lancet Infectious Diseases.

“In a context where over 90% of SARS-CoV-2 infections were caused by Omicron BA.5, a second booster of an mRNA vaccine conferred additional protection against severe COVID-19 for the first 4 months post-administration compared with receiving only a first booster at least 120 days earlier (median time of 9 months), which is the time when a person is eligible to receive a second booster in Italy, given that the protection induced by the first booster dose has likely waned after 120 days,” Mateo-Urdiales and co-authors wrote.

“Further research, based on a longer follow-up time and conducted in a calendar period with predominant circulation of the Omicron subvariant XBB (currently predominant in Italy), is recommended to gain more information for adequately planning the timing of booster dose administration,” they concluded.

There were no relevant differences in rVE with a booster dose of the bivalent BA.4/5 vaccine in adults ages 60 to 79 and those 80 and older. Overall, in the 14 to 118 days post-administration, rVE among the 60-79 age group was 53.6% compared with 48.3% in those 80 and older.

The researchers estimated that the number needed to vaccinate to prevent one case of severe COVID-19 over 4 months was 535 in the overall population, and 887 in the 60-79 age group and 233 in the 80 and older age group.

They also pointed out that slightly higher rVE was seen when the definition of severe outcomes was narrowed specifically to COVID deaths and hospital admissions (53.1%).

While the findings on waning vaccine protection “could reflect a better match between the spike protein antigen targeted in the bivalent vaccine and the predominantly circulating Omicron BA.5 sublineage in Italy at the time, caution needs to be exercised in interpreting these results as showing evidence for superior effectiveness of the bivalent vaccines,” wrote Shabir Madhi, MBBCh, PhD, of the University of the Witwatersrand in Johannesburg, and Daniel Feikin, MD, of the World Health Organization, in an editorial comment.

“The ideal comparative vaccine effectiveness estimates between monovalent and bivalent COVID-19 vaccine boosters would be a setting where both vaccines are used contemporaneously in a non-targeted manner,” they noted, pointing out that the magnitude of the differences between monovalent and bivalent vaccines in the current Italian study is, at least in part, potentially due to residual confounding, particularly since the outcome was severe COVID-19 disease, where there has been less reduction in vaccine-induced protection against Omicron due to the relative preservation of cellular immune response against Omicron that is induced by ancestral-virus monovalent COVID-19 vaccines.”

“Time-varying confounding would also affect evaluations of the effectiveness of future COVID-19 vaccines, including the recommended XBB-containing monovalent vaccines currently being developed,” they added. “Hence, comparisons of newer COVID-19 vaccine formulations in relation to earlier vaccine formulations should be interpreted in light of the potential for similar time-variant confounding.”

For this study, Mateo-Urdiales and colleagues used data from the Italian vaccination registry and the SARS-CoV-2 surveillance system from September 2022 to January 2023. They matched 2,129,559 adults ages 60 and up receiving a second booster 1:1 with a person who had received the first booster only at least 120 days earlier.

The study population consisted of 116,822 participants who received second doses of a monovalent booster, 670,496 who received a BA.1-containing bivalent, and 1,342,241 who received a BA.4/5-containing bivalent. Slightly over half of participants were women; median age was 74 in the monovalent booster group and 73 in the bivalent booster groups. In each group, 15% of participants were considered high risk, including residents in long-term care facilities and those with relevant comorbidities.

The researchers noted that their study was limited by unmeasured, unknown characteristics that were not accounted for, as well as likely underestimated infections. In addition, waning protection may be underestimated for the BA.4/5 booster, since the time interval post-vaccination was shorter than the other booster groups. Moreover, there may have been other COVID strains circulating.

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