A fourth dose of the bivalent (two-strain) COVID-19 vaccine is substantially more effective against medical treatment and hospitalization than a fourth monovalent (single-strain) dose among both previously infected and never-infected people who had received three monovalent doses, concludes an observational study published yesterday in The Lancet Infectious Diseases.
A team led by Singapore Ministry of Health researchers used national healthcare data to retrospectively compare the effectiveness of a fourth dose of the bivalent or monovalent COVID-19 vaccine against medical treatment and hospitalization among 2,749,819 adults from October 14, 2022, to January 31, 2023, by previous infection status.
Most participants had received three monovalent doses and were eligible for a fourth dose, and 31.1% received a fourth dose before the study began. Median age was 44 years.
The monovalent vaccine targets wild-type SARS-CoV-2, and the bivalent replacement targets both the wild-type virus and the Omicron variant. The bivalent Pfizer/BioNTech vaccine targets the Omicron BA.4/BA.5 subvariant, while the Moderna version targets the BA.1 subvariant.
Older people benefitted most from bivalent dose
Of the 2,749,819 adults, 129,870 medically attended symptomatic COVID-19 infections were recorded, 21.6% of which were reinfections. A total of 2.5% of participants with first infections and 2.0% with reinfections required hospitalization. Of them, 0.4% with first infections and 0.2% with reinfections required supplemental oxygen or intensive care or died.
A fourth monovalent COVID-19 vaccine dose didn't confer more protection than three doses against symptomatic infection among never-infected participants (hazard ratio [HR], 1.09), while dose 4 of the bivalent vaccine did (HR, 0.18, or 82% protection). The HRs were 0.87 (13% protection) and 0.14 (86% protection) among previously infected participants after four monovalent and bivalent doses, respectively.
Four doses of the bivalent vaccine offered more protection against hospitalization to both never-infected and previously infected participants than four monovalent doses (bivalent HRs, 0.12 and 0.04, respectively, vs monovalent HRs, 0.84 and 0.85, respectively).
No waning of bivalent vaccine effectiveness against medical treatment was seen after 2 months among both previously infected and never-infected participants.
The bivalent Pfizer vaccine targeting BA.4/BA.5 was more effective than the Moderna version (HRs, 0.04 [96% protection] vs 0.25 [75% protection], respectively). The monovalent and bivalent vaccines were similarly effective against medical treatment among adults aged 18 to 49 years, but a fourth bivalent dose conferred substantially more protection than a fourth monovalent dose among those 50 years and older.
Boosters with an omicron-adapted bivalent mRNA vaccine could be recommended for additional protection against emerging omicron variants, even in populations with high levels of hybrid immunity.
The number needed to vaccinate with the fourth bivalent dose to prevent one medically attended COVID-19 infection was 40 people in the never-infected group and 85 among the previously infected. The number needed to vaccinate to prevent one hospitalization was 1,488 people in the COVID-naïve group and 3,808 in the previously infected group.
Benefits even for those with hybrid immunity
"Boosters with an omicron-adapted bivalent mRNA vaccine could be recommended for additional protection against emerging omicron variants, even in populations with high levels of hybrid immunity," the study authors wrote, referring to populations with both vaccinated and previously infected people.
In a commentary in the same journal, Ronen Arbel, PhD, and Yael Wolff-Sagy, PhD, both of Clalit Health Services in Israel, said the study contributes knowledge to some of the most crucial COVID-19 vaccine policy questions faced by healthcare systems.
These questions include whether other countries should join the United States in discontinuing use of the monovalent vaccines ("The answer seems to be yes"), whether young adults and those with hybrid immunity should continue to be vaccinated, and whether infection is an important outcome in the Omicron era.
"Vaccinating younger adults should be considered if the prevention of medically attended symptomatic SARS-CoV-2 infections is deemed useful," Arbel and Wolff-Sagy wrote.
"The medically attended symptomatic SARS-CoV-2 infections measure seems to provide a more reliable and valuable alternative [to infection] in this era of asymptomatic SARS-CoV-2 infections, under-testing, and under-reporting of infections," they added.
