Effectiveness of A Fourth Dose of COVID-19 mRNA Vaccine in the Elderly Population During the Omicron BA.2 and BA.5 Circulation: A Nationwide Cohort Study in Korea (K-COVE)

Abstract

We estimate the effectiveness of a fourth dose booster of coronavirus disease 2019 mRNA vaccine in individuals aged ≥60 years during Omicron BA.2 and BA.5 circulation in Korea. The effectiveness against critical infection was 67.7% (95% confidence interval, 50.7%–78.8%) at 31–60 days and 62.1% (95% confidence interval, 45.5%–73.7%) at 61–90 days.

Effectiveness of 4th dose booster of COVID-19 mRNA vaccine in Korean adults aged >=60 years during Omicron BA.2 and BA.5 circulation against critical infection was 67.7% (95% CI 50.7%–78.8%) at 31–60 days and 62.1% (45.5%–73.7%) at 61–90 days.

Elderly individuals aged 60 years and above are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes. Previous studies have shown that coronavirus disease 2019 (COVID-19) vaccination is effective at preventing severe risk and death in elderly populations [1]. However, whether vaccines have clinical utility during the Omicron BA.2 and BA.5 period is unclear.

In South Korea, introduction of COVID-19 vaccines began in February 2021, resulting is an estimated vaccine effectiveness (VE) of 63% against all infection, 93% against severe disease, and 95% against death [2]. Since April 14, 2022, the fourth dose booster of the COVID-19 mRNA vaccines has been introduced for individuals aged 60 years and older, during the period when 100% of circulating strain was Omicron BA.2 and BA.5.

In this study, we estimate the VE of the fourth dose booster of COVID-19 mRNA vaccine versus a third dose in vaccinated individuals aged 60 years and older against all infection, critical infection, and death during the SARS-CoV-2 Omicron BA.2 and BA.5 predominant period.

METHODS

This was a retrospective cohort study based on nationwide registry data. We used national immunization registry linked to surveillance data that captures 100% of immunization data and laboratory-confirmed COVID-19 cases in Korea. The large, linked database was formed to create a national cohort to evaluate vaccine effectiveness in Korea (Korea COVID-19 Vaccine Effectiveness [K-COVE]). A detailed summary of the data set was described previously [3]. The input of the K-COVE dataset was made upon epidemiological investigation in individual cases reported as SARS-CoV-2.

From the target population of 54 148 484 (total Korean population, across the nation), we excluded persons aged <60 years, long-term care residents, immunocompromised persons, those who received the third dose vaccination after April 14, 2022, those who received less than 3 doses of vaccines, prior SARS-CoV-2 infections, those who received Janssen or Novavax vaccines, imported cases, and registry errors (Supplementary Figure 1). Individuals were classified as third dose or fourth dose vaccinated after vaccine uptake of the respective dose. The observed time frame was from April 14, 2022 to August 20, 2022.

The outcome of this study was all infections (irrespective of symptoms), critical infections (requiring noninvasive or invasive mechanical ventilation, extracorporeal membrane oxygenation, or continuous renal replacement therapy), and deaths (attributable to COVID-19, cause of death determined by treating physician) after baseline (14 days postvaccination) until August 20, 2022.

To compare the risk of outcomes based on vaccination status (third vs fourth dose), a time-dependent Cox proportional hazard model was used to calculate hazard ratios (HRs), and the 95% confidence interval (CI) was estimated using robust standard errors to adjust for the matched cohorts to calculate VE at 0–14 days, 15–30 days, 31–60 days, and 61–90 days after days of last dose administration of vaccine [VE = (1-HR)×100]. All statistical analyses were conducted using R v.4.02 (R Core Team, Vienna, Austria). The study was approved by the Korea Disease Control and Prevention Agency Institutional Review Board (IRB No. 2021-12-03-PE-A).

RESULTS

Between April and August 2022, a total of 4 698 503 persons with third dose and 3 152 078 persons with fourth dose mRNA vaccinations were included (Table 1). Median age was lower in third dose group than in fourth dose group (66 vs 73 years), and percentage of persons who received AstraZeneca vaccine as their primary series was higher in the third dose group than in the fourth dose group (72.5% vs 54.7%).

Table 1.

Participants’ Characteristics at Baseline by Vaccination Status at the End of the Follow-up Period, Cohort Age ≥60 Years, K-COVE, April–July 2022 (n = 7 850 581)

Characteristics	Third Dose		Fourth Dose
	N = 4 698 503		N = 3 152 078
	n	(%)	N	(%)
Age in years, median (IQR)	66 (62–73)		73 (66–79)
Age Group
60–74 years	3 764 120	(80.1)	1 833 297	(58.2)
75–84 years	730 294	(15.5)	1 088 997	(34.5)
85 + years	204 089	(4.3)	229 784	(7.3)
Sex
Female	2 531 191	(53.9)	1 647 448	(52.3)
Male	2 167 312	(46.1)	1 504 630	(47.7)
Regions
Capital area	2 113 773	(45.0)	1 335 228	(42.4)
Noncapital area	2 584 730	(55.0)	1 816 850	(57.6)
Vaccine Types
Primary Series
AstraZeneca	3 407 761	(72.5)	1 723 337	(54.7)
Pfizer	1 138 319	(24.2)	1 360 927	(43.2)
Moderna	69 194	(1.5)	12 588	(0.4)
AstraZeneca-Pfizer	83 221	(1.8)	55 225	(1.8)
Moderna-Pfizer	8	-	1	-
Third Dose
Pfizer	2 175 008	(46.3)	1 799 138	(57.1)
Moderna	2 523 495	(53.7)	1 352 940	(42.9)
Fourth dOse
Pfizer	-	-	2 817 451	(89.4)
Moderna	-	-	334 627	(10.6)

Abbreviations: COVID-19, coronavirus disease 2019; IQR, interquartile range; K-COVE, Korea COVID-19 Vaccine Effectiveness Study.

The fourth dose VE against all infection was 35.3% (95% CI, 34.4–36.2) at 15–30 days, which decreased to 17.3% (95% CI, 16.6–18.0) at 61–90 days (Figure 1 and Supplementary Table 1). The fourth dose VE against critical infection and death at 15–30 days were higher at 70.6% (95% CI, 55.4–80.6) and 82.8% (95% CI, 62.9–92.0), respectively. By 61–90 days, the VE against critical infection remained at 62.1% (95% CI, 45.5–73.7) and the VE against death was 63.9% (95% CI, 35.9–79.7).

Figure 1.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in the elderly population during Omicron BA.2 and BA.5 circulation against (A) all infection, (B) critical infection, and (C) death. VE, vaccine effectiveness.

DISCUSSION

Using a national cohort of the population 60 years and older, we estimated a high VE of the fourth dose COVID-19 mRNA in preventing COVID-19-related critical infection (VE = 62.1%) and deaths (VE = 63.9%) during the period of BA.2, and BA.5 circulation, compared with the third dose vaccination. Our estimate is in line with the ones reported for adults aged 60 years or older in Israel (VE = 68% against hospitalization, VE = 74% against death) [4]. In Sweden, fourth dose of mRNA vaccine was associated with sustained protection against SARS-CoV-2 infection for approximately 4 months; resulting in reduced risk of death from all causes in residents of long-term care facilities and in the oldest old persons [5]. Nonetheless, the protection against Omicron from fourth dose vaccination was evident, even when comparing with the third dose: a Canadian study suggested a VE of 49% against infection, 69% against symptomatic infection, and 86% against severe infection [6]. The forth dose booster vaccination, irrespective of subvariant types of SARS-CoV-2 Omicron, was associated with the highest protection, as shown in previous studies [7]. In addition to these findings, our study showed the protective effectiveness of the fourth dose mRNA vaccination against BA.2 and BA.5 in the Asian setting.

There are several limitations to this study. First, not all positive cases during the outcome period may have been identified, because many asymptomatic Omicron infections may have occurred. Moreover, lower positive predictive value of the rapid antigen test during the observed period may have led to an underestimation of infection. Second, protection from the fourth dose vaccinated persons might be overestimated if exposed people were more likely than unexposed people to get tested. In addition, the vulnerable subpopulation, including persons who are immunocompromised and residents in long-term care facilities, were not included; therefore, our finding may not be generalizable to these groups. Finally, the difference in type of vaccines received may have affected the result, which was not measured in this study. Despite these limitations, our finding provides evidence-based information about the fourth dose COVID-19 vaccination during the Omicron BA.2 and BA.5 predominant period.

CONCLUSIONS

In conclusion, our study found that a fourth dose booster vaccination offers additional protection against critical infection and death during the Omicron BA.2 and BA.5 predominant period in elderly population.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.