Effectiveness of COVID-19 XBB.1.5 monovalent mRNA vaccine in Korea: interim analysis

As coronavirus disease-2019 (COVID-19) becomes an endemic disease, the virus continues to evolve and become immunologically distinct from previous strains. Immune imprinting has raised concerns about bivalent mRNA vaccines containing both ancestral virus and Omicron variant. To increase efficacy against the predominant strains as of the second half of 2023, the updated vaccine formulation contained only the mRNA of XBB.1.5 sublineage. We conducted a multicenter, test-negative, case-control study to estimate XBB.1.5 monovalent vaccine effectiveness (VE) and present the results of an interim analysis with data collected in November 2023. Patients who underwent COVID-19 testing at eight university hospitals were included and matched based on age (19-49, 50-64, and ≥65 years) and sex in a 1:1 ratio. VE was calculated using the adjusted odds ratio derived from multivariable logistic regression. Of the 992 patients included, 49 (5.3%) received the XBB.1.5 monovalent vaccine at least 7 days before COVID-19 testing. Patients with COVID-19 (cases) were less likely to have received the XBB.1.5 monovalent vaccine (case 3.5% vs. control 7.2%, p=0.019) and to have a history of COVID-19 within 6 months (2.2% vs. 4.6%, p=0.068). In contrast, patients with COVID-19 were more likely to be healthcare workers (8.2% vs. 3.0%, p=0.001) and to have chronic neurological diseases (16.7% vs. 11.9%, p=0.048). The adjusted VE of the XBB.1.5 monovalent mRNA vaccine was 56.8% (95% confidence interval: 18.7-77.9%). XBB.1.5 monovalent mRNA vaccine provided significant protection against COVID-19 in the first one to two months after vaccination.


Introduction
Since its first emergence in late 2019, the ever-changing nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made previous immunity acquired through infection or vaccines based on ancestral SARS-CoV-2 less effective.This immune evasion became more apparent with the emergence of the Omicron variant and its sublineages since late 2021 (1)(2)(3).To combat this, bivalent vaccines containing the mRNA of both ancestral SARS-CoV-2 and Omicron variant were administered as a booster shot in 2022.However, near-total replacement of the ancestral SARS-CoV-2 by the Omicron variant and the phenomenon of immune imprinting have raised questions about the utility of including the mRNA of the ancestral SARS-CoV-2 in future coronavirus disease 2019 (COVID- 19) vaccines (4)(5)(6)(7)(8).
In mid-2023, the World Health Organization and the United States (US) Food and Drug Administration advised pharmaceutical companies to only include component of the XBB lineage ("monovalent") in the updated COVID-19 vaccines for the 2023/ 2024 season (9,10).XBB-monovalent vaccines were also recommended by the Advisory Committee on Immunization Practices for the corresponding season, serving as both a booster dose and primary series, for all persons aged six months or older (11).
Similar to influenza vaccines, vaccine efficacy reports are not required for these updated vaccines before authorization.Although it has become essential to monitor the effectiveness of COVID-19 vaccines, studies on this matter are scarce.To fill this knowledge gap, we aimed to investigated COVID-19 XBB.1.5monovalent mRNA vaccine effectiveness in Korea.This is an interim analysis of data collected through a network of tertiary teaching hospitals created to monitor respiratory infectious diseases since 2011 (12).

Methods
This is a retrospective, multicenter, test-negative, case-control study.Patients aged 19 years or older who underwent COVID-19 testing at eight participating hospitals (mostly located in the Seoul Metropolitan Area) were included.Individuals who were tested for COVID-19 as part of pre-admission surveillance (i.e., without clinical or epidemiological risk factors for COVID-19) were excluded.Cases were defined as patients who tested positive for COVID-19 using reverse transcription polymerase chain reaction (RT-PCR) or a lateral flow assay with nasopharyngeal swab samples.Those that tested negative were classified as controls.The limit of detection for the RT-PCR test and RAT we used is 5,000 copies/mL and 2.5×10 1.8 TCID 50 /mL, respectively.For SARS-CoV-2, 2.5×10 1.8 TCID 50 /mL falls in the range between 5×10 5 -1×10 6 copies/mL (13).The LOD value of RAT meets the WHO requirement of 100-1,000 TCID 50 /mL.For this interim analysis, data collected in November 2023 were included.
The case and control groups were matched based on age (19-49, 50-64, and ≥65 years) and sex in a 1:1 ratio.Information on demographics, COVID-19 vaccination history, recent history of COVID-19, comorbidities, symptoms, and clinical outcomes was collected through chart review.The vaccination status was verified using the National Immunization Registry of the Korean Disease Control and Prevention Agency.The vaccine was considered effective if administered at least seven days before the date of COVID-19 testing.In Korea, two mRNA vaccines were available (Comirnaty Omicron XBB.1.5,Spikevax XBB.1.5)since October 19, 2023.Comirnaty and Spikevax are mRNA vaccines manufactured by Pfizer-BioNTech (New York, NY, USA and Mainz, Germany) and Moderna (Cambridge, MA, USA), respectively.Each vaccine contains 30 mg/0.3mL and 50 mg/0.5mL of mRNA encoding the spike protein of SARS-CoV-2 Omicron XBB.1.5sublineage.Both vaccines were administered intramuscularly.
Categorical variables were compared using the chi-square test or Fisher's exact test.In addition to receipt of the XBB.1.5monovalent vaccine, the following variables were included in the multivariable logistic regression: age, sex, comorbidities, receipt of bivalent vaccination in 2022, recent history of COVID-19, and being a healthcare worker.We then removed variables with p values greater than 0.15 from the multivariable model (backward selection).Multicollinearity between variables was defined as a variance inflation factor greater than 10.The goodness of fit of the regression model was examined using the Hosmer-Lemeshow test.Vaccine effectiveness (VE) was calculated using the adjusted odds ratio derived from the multivariable logistic regression (1adjusted odds ratio).Statistical significance was defined as p < 0.05.Statistical analyses were performed using the R software (version 4.3.1;R Foundation, Vienna, Austria).

Discussion
We found that the XBB.1.5monovalent mRNA vaccine conferred significant protection against COVID-19 in the first As it has become clear that COVID-19 is here to stay despite rapid development and distribution of effective vaccines, questions regarding future vaccination strategies have been raised.To improve immunogenicity against the immune-evasive Omicron variant and its sublineages, the first updated "bivalent" vaccine was developed in 2022.However, the bivalent vaccine did not appear to have better immunogenicity against the Omicron variant than the monovalent vaccine based on the ancestral SARS-CoV-2 (7,15).This has led to the development of XBBbased monovalent vaccines in 2023 to increase the XBB antigen dose and avoid immune imprinting.To date, studies on this novel COVID-19 vaccine are limited.The only study that compared the immunogenicity of XBB.1.5monovalent and bivalent (XBB.1.5and BA.4/5) mRNA vaccines found that the monovalent vaccines were not significantly more immunogenic than the bivalent vaccine (16).Because this study was not powered to detect statistical significance, whether a monovalent vaccine would be a better choice in the future remains uncertain.
In addition to the controversy surrounding antigen doses in updated vaccines, there is an ongoing debate regarding the necessity of annual update of the COVID-19 vaccine itself.XBB.1.5monovalent mRNA vaccines are immunogenic against emerging Omicron sublineages, including EG.5.1, HV.1, and JN.1 (16,17).Our findings are consistent with this, considering HK.3 and EG.5 accounted for 87% of circulating sublineages during the study period (18).While studies conducted to date, including ours, suggested that XBB.1.5monovalent vaccines were effective in preventing laboratory-confirmed COVID-19 or COVID-19related hospitalization, cautious interpretation is needed because all of these studies only included the early post-vaccination period (14,19,20).More data from longer observation periods are required to establish future vaccination strategies.
There was a remarkable difference in the number of patients who experienced COVID-19-related symptoms between the case and control group.Symptoms that occurred more frequently in the control group were dyspnea (case 64 [14%] vs. control 129 [28%]) and chest discomfort (case 9 [2%] vs control 40 [9%]).This may be partly explained by the greater number of patients with chronic lung disease in the control group (case 14 [3%] vs. control 39 [9%]).Other respiratory pathogens such as influenza virus, respiratory syncytial virus, adenovirus and Mycoplasma pneumoniae that had been circulating in the community during the study period could have been the cause as well (21).
This study has several limitations.First, owing to the retrospective nature of the study, some confounders may have remained unadjusted.Second, we did not collect data on the exact number of prior COVID-19 vaccinations, which may have been a protective factor.However, this effect is likely to be small because 1) most Korean adults had completed primary series vaccination (96.6% were vaccinated twice and 75.2% three times as of October 28, 2022); 2) 78.6% of the Korean population had acquired natural immunity by contracting COVID-19 (due to any SARS-CoV-2 variant) as of August 31, 2023, which seems to be an undercount; and 3) neutralizing antibody levels after vaccination or infection wane after several months, making remote vaccination or infection less protective, especially less severe ones (22)(23)(24)(25).Third, although the control group exclusively comprised symptomatic individuals, the case group included some asymptomatic persons (close contacts with COVID-19 cases), making the two groups less comparable in terms of healthcare-seeking behaviors.Fourth, the use of lateral flow assay, which is less sensitive than RT-PCR, may have overlooked some COVID-19 cases.In conclusion, the XBB.1.5monovalent mRNA vaccine provided significant protection against COVID-19 in the first month after vaccination.Full analysis results will be followed.

TABLE 1
Baseline characteristics of study population.
month after vaccination.To the best of our knowledge, this is the first study on XBB.1.5monovalent VE against symptomatic COVID-19 outside the US as of February 5, 2024, at which this manuscript was submitted for publication.Our results are in line with the most recent US study, which reported 54% of early VE estimate in adults (14).

TABLE 2
Clinical outcomes of study population.

TABLE 3
Results of multivariable logistic regression analysis.