Introduction
The omicron variant still causes many cases of severe COVID-19 and death.
Booster immunisation with SARS-CoV-2 monovalent mRNA vaccines has shown high effectiveness against COVID-19 caused by the earlier variants of SARS-CoV-2.
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A second monovalent mRNA vaccine booster dose, provided during the omicron-dominant SARS-CoV-2 wave, has been shown to substantially reduce hospitalisations and deaths due to COVID-19.
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However, the monovalent mRNA booster vaccine effectiveness against omicron was lower than that observed for against other SARS-CoV-2 variants,
- Thompson MG
- Natarajan K
- Irving SA
- et al.
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and the beneficial effect has been shown to wane substantially at 3–4 months after vaccination.
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Vaccination is the primary tool for avoiding severe COVID-19. Therefore, there is great interest in new types of vaccines containing different variants of SARS-CoV-2, which could induce broader immune responses and provide enhanced protection against severe outcomes.
The bivalent vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the omicron BA.4 and BA.5 sublineages. This approval was based only on safety and immune response data for the bivalent booster,
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and previous safety and effectiveness data for the monovalent booster.
Since September, 2022, bivalent mRNA vaccines have replaced monovalent boosters in the USA, Israel, and other countries. The bivalent mRNA booster vaccines are currently prioritised in Israel for people at high risk of severe COVID-19, primarily those aged 65 years or older.
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To date, randomised controlled trials evaluating the clinical efficacy of a bivalent mRNA booster vaccine are unavailable. We aimed to evaluate the effectiveness of a bivalent mRNA vaccine booster dose to prevent hospitalisations and deaths due to COVID-19.
Evidence before this study
Bivalent mRNA COVID-19 vaccination booster doses containing an omicron (B.1.1.529) sublineage component have been approved by the US Food and Drug Administration (FDA) for emergency use since September, 2022, and are currently used globally. The vaccine effectiveness of bivalent vaccination booster doses in preventing severe COVID-19 outcomes has not been established by randomised trials. We searched Google Scholar and PubMed on Feb 2, 2023, for real-world COVID-19 bivalent vaccine effectiveness studies published between Sept 1, 2022 (the day after the FDA approval of the bivalent vaccines) and Jan 31, 2023, with no language restrictions, using the terms “Bivalent vaccine” OR “Bivalent COVID-19 vaccine” OR “Bivalent booster vaccine” OR “Bivalent omicron” OR “mRNA bivalent booster” OR “mRNA bivalent booster”. We included only research regarding mRNA COVID-19 vaccines and included only peer-reviewed research. We found three reports from the US Centers for Disease Control and Prevention (CDC) that evaluated the effectiveness of a bivalent mRNA vaccine booster dose. The first, published on Dec 2, 2022, analysed 360 626 COVID-19 tests done at retail pharmacies for adults who reported symptoms consistent with COVID-19 at the time of testing. In this analysis, bivalent mRNA vaccine booster doses provided additional protection against symptomatic COVID-19. However, this report did not analyse the vaccine’s effectiveness in reducing hospitalisations and deaths due to COVID-19. A second report from the CDC included 798 patients aged 65 years or older who were admitted to hospital with illness that was consistent with COVID-19. This case-control analysis used a test-negative design to compare patients who received a bivalent mRNA vaccine booster dose with patients who had received a series of at least two monovalent mRNA vaccine doses. The relative vaccine effectiveness of the bivalent booster dose in reducing COVID-19-related hospitalisations was 73% (95% CI 52–85). Another analysis from the CDC that included 78 303 patients who had an emergency department or urgent care encounter or hospitalisation with an illness that was consistent with COVID-19 concluded that bivalent mRNA vaccines administered after at least two monovalent doses provided 32–54% additional protection against COVID-19-related emergency deprtament and urgent care encounters and hospitalisations compared with past monovalent vaccination only. However, neither of these analyses evaluated vaccine effectiveness in reducing deaths due to COVID-19. A large study from North Carolina, USA, published as a correspondence, compared the effectiveness of the monovalent mRNA booster vaccine provided from May 25 to Aug 31, 2022, with the effectiveness of the bivalent booster provided from Sept 1 to Nov 3, 2022, both from day 15 to day 99 after receipt of the booster dose. In this study, in participants aged 65 years or older, the vaccine effectiveness against severe COVID-19 resulting in hospitalisation after receipt of one monovalent booster dose was 21·0% (95% CI –7·7 to 42·1), compared with 58·8% (43·0 to 70·2) after one bivalent booster dose. Vaccine effectiveness against severe COVID-19 resulting in hospitalisation or death was 20·3% (95% CI –6·0 to 40·1) for the monovalent booster dose compared with 61·5% (47·1 to 71·9) for the bivalent booster dose. Results for death alone were not reported in this study.
Added value of this study
To our knowledge, this study is one of the first to evaluate the real-world effectiveness of the bivalent mRNA vaccine booster dose to reduce hospitalisations or deaths due to COVID-19, when compared with people who were eligible for the vaccine but who were not vaccinated during the study period. Our findings suggest that, in adults aged 65 years or older, the vaccine effectiveness of the bivalent mRNA vaccine booester dose is 72% (95% CI 60–81) for COVID-19 related hospitalisation and 68% (42–82) for COVID-19-related death.
Implications of all the available evidence
Bivalent mRNA booster vaccination in adults aged 65 years or older is an effective and essential tool to reduce their risk of hospitalisation and death due to COVID-19. Vaccination remains the primary tool for avoiding severe COVID-19. Our findings highlight the importance of new types of vaccines containing different variants of SARS-CoV-2, which are likely to induce broader immune responses and provide enhanced protection against severe outcomes.
Methods
Study design and participants
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The bivalent mRNA vaccine administered in Israel was the Pfizer-BioNTech COVID-19 vaccine (BA.4 and BA.5). The study observation period commenced on Sept 27, 2022, 7 days after the bivalent vaccination campaign was initiated in CHS, and ended 120 days later on Jan 25, 2023. The data extraction date was Jan 29, 2023.
The study cohort included all CHS members who were aged 65 or older and eligible for a bivalent mRNA COVID-19 booster vaccination. Per the Israeli Ministry of Health (IL-MOH) guidelines, the eligibility criteria were that participants must have had at least 3 months since receiving the last vaccination, had at least 3 months since the last SARS-CoV-2 infection, and completed the primary two-dose monovalent mRNA vaccination series. The CHS Institutional Helsinki and Data Utilization Committees approved the study.
Procedures
The vaccine was administered at no charge in all participants who opted to receive it.
The primary endpoint was hospitalisation due to COVID-19, which we compared between participants who received a bivalent mRNA booster vaccination and those who did not. The secondary endpoint was death due to COVID-19. Hospitalisations and deaths due to COVID-19 among participants who received the bivalent vaccine were compared with those who did not receive a bivalent booster.
For each participant, we extracted demographic data on age, sex, geographical district of primary health-care clinic, population sector (general Jewish, Arab, and ultra-Orthodox Jewish), and score for socioeconomic status. Data on previous immunity factors, including COVID-19 vaccinations and SARS-CoV-2 infections, were collected from reports of the central COVID-19 database of the IL-MOH (COVID-19 vaccination dates and vaccine type, PCR tests, and state-regulated rapid antigen test dates and results). Hospitalisations and deaths due to COVID-19 were reported by the hospitals according to the IL-MOH guidelines. The definition of hospitalisation due to COVID-19 was based on the patient’s primary diagnosis in the discharge letter, and the definition of death due to COVID-19 was based on the primary diagnosis on the death certificate.
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were also collected, which included BMI, smoking status, and history of diabetes, chronic obstructive pulmonary disease, asthma, chronic renal failure, lung cancer, hypertension, ischaemic heart disease, chronic heart failure, obesity, stroke, and transient ischaemic attack.
Statistical analysis
Descriptive statistics were used to characterise the study participants. Because the independent variable (bivalent booster vaccination) varied over time, appropriate univariate and multivariable survival analyses were done with time-dependent covariates. All covariates were tested for interactions with the variable of interest (bivalent booster vaccination). The proportional hazards assumption was tested for each variable by comparing survival curves and performing Schoenfeld’s global test.
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To allow for censoring, we used a multivariable Cox proportional hazards regression model with time-dependent covariates adjusted for sociodemographic and previous immunity factors and coexisting illnesses to estimate the association between all covariates and bivalent mRNA booster vaccination uptake, COVID-19-related hospitalisations, and COVID-19-related deaths.
participants were transferred from the risk set who had not received a bivalent booster vaccination to the risk set who had received a bivalent booster vaccination at 7 days after receiving the vaccination, modifying their vaccination status from non-recipient to recipient. Consequently, the follow-up of participants who received a bivalent booster vaccination started at the end of the immortal period and lasted for a minimum of 14 days to allow sufficient time for hospitalisation events.
R (version 3.5.0) was used for the univariate and multivariable survival analysis with time-dependent covariates. SPSS (version 26) was used for all other statistical analyses. A two-sided p value of less than 0·05 was considered to indicate significance in all analyses.
Role of the funding source
There was no funding source for this study.
Results
Table 1Baseline characteristics
Data are mean (SD), median (IQR), or n (%).
Table 2Multivariable regression for bivalent booster vaccine uptake
Table 3Multivariable regression for risk of hospitalisation due to COVID-19
FigureCumulative risk of hospitalisation due to COVID-19 by bivalent mRNA booster vaccination status
Table 4Multivariable regression for risk of death due to COVID-19
Table 5Number needed to vaccinate with bivalent booster to prevent one event
Discussion
Our results show that the vaccine effectiveness (calculated as 100 × [1–HR]) of a bivalent BA.4 and BA.5 mRNA vaccine booster dose among eligible adults aged 65 years or older is 72% (95% CI 60–81) for hospitalisation due to COVID-19 and 68% (95% CI 42–82) for death due to COVID-19.
The low uptake might be due to various reasons, including an absence of evidence on the bivalent vaccine’s effectiveness in preventing severe COVID-19 events, vaccine misinformation, reports of side-effects, or the belief that the vaccine is unnecessary as COVID-19 infection is sufficient to obtain immunity.
The much higher number needed to vaccinate for the bivalent vaccine was primarily due to lower vaccine effectivness and higher HR for reducing deaths due to COVID-19 compared with the monovalent booster (0·32 vs 0·10 for the first monovalent booster).
In this analysis, bivalent mRNA booster doses provided additional protection against symptomatic COVID-19, with relative benefits increasing with time since receipt of the most recent monovalent vaccine dose. However, this report did not analyse vaccine effectiveness in avoiding hospitalisations and deaths due to COVID-19.
Another analysis from the CDC that included 78 303 patients who had an emergency department or urgent care encounter or hospitalisation with an illness that was consistent with COVID-19 concluded that bivalent mRNA vaccines administered after at least two monovalent doses provided 32–54% additional protection against COVID-19-related emergency department and urgent care encounters and hospitalisations compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose.
However, these analyses did not evaluate vaccine effectiveness in avoiding deaths due to COVID-19.
In this study, in participants aged 65 years or older, the vaccine effectiveness against severe COVID-19 resulting in hospitalisation after receipt of one monovalent booster dose was 21·0% (95% CI –7·7 to 42·1), compared with 58·8% (43·0 to 70·2) after one bivalent booster dose. Vaccine effectiveness against severe COVID-19 resulting in hospitalisation or death was 20·3% (95% CI –6·0 to 40·1) for the monovalent booster dose compared with 61·5% (47·1 to 71·9) for the bivalent booster dose. Results for death alone were not reported in this study.
Our study has some noteworthy limitations. The primary limitation is that a relatively low number of COVID-19 related hospitalisations, and even fewer COVID-19-related deaths, were observed during the study period. However, our study provides important primary evidence that might further drive engagement of patients and their health-care providers in vaccination. Future studies with longer observation times and more events are warranted.
Our study does not provide evidence regarding comparing the bivalent booster dose to providing an additional monovalent booster dose, because the monovalent mRNA booster was not administered in Israel in parallel with the bivalent formulation during the study period.
The data on COVID-19 infections in Israel during the study period are incomplete for various reasons; for example, some infections were asymptomatic and some were self-diagnosed by home antigen tests, which are not recorded in the CHS database. Therefore, we could not assess the vaccine effectiveness of the bivalent mRNA booster to reduce infection.
However, it should be noted that those study results were not confirmed in the omicron-dominant era.
As in any retrospective cohort study, confounding clinical and sociodemographic characteristics, which might affect the risk of severe outcomes, might have biased the observed effectiveness. We attempted to overcome these biases by adjusting for the variables known to affect the risk of severe COVID-19. However, some sources of bias might not have been measured or corrected adequately, such as social dissimilarities and different behaviour patterns between participants who chose early on to receive the bivalent booster vaccine and those who decided not to. The main demographic groups in Israel (general Jewish population, ultra-Orthodox Jewish population, and Arab population) also manifest different health-related behavioural patterns. Bivalent booster vaccine uptake was significantly lower in the minority Arab and ultra-Orthodox Jewish groups than in the generally Jewish population. However, our analysis adjusted for these subpopulations to overcome such possible bias.
Our analysis included only the Pfizer-BioNTech bivalent mRNA vaccine, as it was the primary supplier in Israel during the study period. Generalisation of these results to other bivalent booster vaccines should be done with caution.
In conclusion, our results suggest that the bivalent mRNA vaccine booster dose is associated with a reduced risk of severe COVID-19 outcomes in adults aged 65 years or older. Our findings highlight the importance of bivalent booster vaccination in populations at high risk of severe COVID-19 and the necessity to increase efforts to encourage eligible people to be vaccinated.
RA, AP, NB, and DN were responsible for the study conceptualisation. TB and RS curated the data. RS, RA, and NB did the formal data analysis. AP, TB, HD-B, and NB were responsible for the investigation. RS, MF, and NB were responsible for the methodology and provided statistical expertise. RA, AH, DN were responsible for the project administration. NB and DN were responsible for the resources. RS was responsible for software. NB and DN supervised the study procedures. SY validated the data. RA wrote the original draft of the manuscript. AP, AH, TB, HD-B, SY, NB, and DN reviewed and edited the manuscript. RA and RS directly accessed and verified the underlying data.
