The Korea Disease Control and Prevention Agency (KDCA) approved of providing a fourth dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (Pfizer mRNA vaccine, Moderna mRNA vaccine or Novavax protein vaccine) for immunocompromised individuals starting from February 14, 2022. Afterward, the vaccination program was extended to individuals over the age of 60 starting from April 14, 2022 and to those aged 50 to 59 and those with underlying diseases starting from July 18, 2022.1 All of these groups were advised to receive their vaccination at least four months after their third dose. These vaccination guidelines of South Korea are similar to those of Israel, which was the first country to implement a fourth vaccination program. However, there was a difference in that the South Korean vaccination guidelines did not include any directions for healthcare workers (HCWs).23

According to studies conducted in countries that have already implemented quaternary vaccines through a national initiative, the fourth dose of SARS-CoV-2 vaccine appears to be helpful in reducing the severity and mortality rate among immunocompromised and elderly people.45 A recent multicenter cohort study of HCWs in Israel reported a breakthrough infection rate of 6.9% for those who received four doses and 19.8% for those who received three doses.6 Based on these results, Cohen et al.6 contended that a fourth dose of vaccine for HCWs could help maintain the function of the healthcare system during the pandemic. However, the South Korean healthcare system is different to those of European countries and the United States. The guidelines for a fourth dose in South Korean HCWs need to be clarified.

We examined the real-world effectiveness of the third dose of vaccine in preventing coronavirus disease 2019 (COVID-19) among South Korean HCWs over eight months, and we simultaneously analyzed the change in titers of neutralizing antibody against the omicron variant (B.1.1.529).

Omicron (B1.1.529) is a variant of SARS-CoV-2 first identified in South Africa on November 24, 2021.9 Omicron is currently prevalent worldwide and continues to mutate into subvariants. Since August 2021, booster or additional doses of vaccines have not been tailored to the new variants of SARS-Cov-2. Although many studies have shown that these vaccines are still helpful in reducing the severity of the disease,2101112 many still question the benefits of additional vaccinations in immune-competent people that had already received pre-existing vaccines.1314

The present study demonstrated that neutralizing antibody titers against the omicron after a third vaccine dose, measured by sVNT inhibition score, tended to gradually decrease over the 8-month follow-up period in healthy South Korean HCWs. However, it is worth noting that 79% of the infected group were infected within the four months following administration of the third dose, during which the immune protection was expected to be sufficient. In addition, the mean period from the third dose to infection in the infected participants was 101.8 ± 30.0 days, and the median value was 97.5 days (Q1/Q3 = 84.8/117.5), while the median follow-up period after the third dose was 246 days (Q1/Q3 = 220.0/246.5). This implies that most infections occurred within a relatively narrow time window, which may be attributable more to the widespread nature of the omicron variant in the community than to the subjects’ humoral immunogenicity at individual levels.

Our study also exhibited a rapid decline of neutralizing antibody % inhibition against omicron in uninfected participants at the 8-month of follow-up; however, the sVNT value tended to be stable in infected participants. The recent resurgence of COVID-19 in South Korea, which has a very high vaccine coverage rate,15 is mainly among previously uninfected individuals,16 and the second wave of the infection is likely to be due to decreased vaccine effectiveness over time. This result suggests the need for a fourth dose of vaccine, in line with previous evidence for the improvement of the SARS-Cov-2 antibody response after a booster dose in uninfected HCWs.17 However, the clinical and practical benefits of more than three doses of vaccine in terms of hybrid immunity, which is defined as the immune protection in individuals who have had one or more doses of a COVID-19 vaccine and experienced at least one SARS-CoV-2 infection before or after the initiation of vaccination, are still questionable.18

The sVNT inhibition score (94.6 ± 4.0, 93.3 ± 4.5) of those infected with SARS-CoV-2 (presumed omicron variant) were higher than the score measured one month after the third-dose vaccination (81.0 ± 20.5) (Table 3). Additionally, it was shown that the sVNT inhibition score of the infected participants remained around 85.9 ± 15.1 even after a mean follow-up period of 136.6 ± 29.2 days since infection (Table 2). This suggests that hybrid immunity might be superior to the current vaccine in terms of neutralizing antibody production capacity and durability. On the other hand, there is some opinion that vaccine induced immunity to omicron variant may be relatively low because current vaccines have been developed for the wild type.19 Future studies on the immunity generated after receiving a bivalent vaccine containing omicron variant antibodies will help to understand this. Our study followed up with participants for about four months after infection, but one epidemiological study in children and adolescents who were previously infected with SARS-CoV-2 has reported that natural immunity protected against re-infection for at least 18 months.20

Recently, interest in hybrid immunity has been increasing.21 Goldberg et al.22 showed that hybrid immunity in individuals who received a single dose of vaccine plus infection was associated with a level of protection similar to that of three doses of vaccine. Zar et al.23 suggested that hybrid immunity formed with one vaccine after infection, including omicron, produced stronger immunogenicity and protection than two doses in a naïve subject. An epidemiological study in Qatar showed that hybrid immunity is effective in preventing re-infection with COVID-19, including omicron, and that protection against severe outcomes such as hospitalization or death was strong regardless of the variants.24 From this point of view, our study included two groups: one with hybrid immunity from an infection after three doses and the other with vaccine induced immunity without previous infection. The degree and duration of immunity these patient groups exhibit against future omicron surges are yet to be known. In fact, as the number of people infected after vaccination or vaccinated after infection increases, research on hybrid immunity is expected to be helpful in planning future vaccination programs.

During the COVID-19 pandemic, most countries around the world have followed the guidelines of the WHO or countries with advanced healthcare systems. However, universal application of these guidelines to countries with different healthcare systems can be impractical and inefficient.25 As suggested by Cohen et al.,6 a fourth dose of vaccine for HCWs may prevent the decline in the effectiveness of the third dose and further outbreaks, thereby contributing to sustainable functioning of healthcare systems during the pandemic. From this point of view, the healthcare system has not been substantially disrupted by the pandemic thus far, and hybrid immunity has demonstrated its enduring protective effect; thus, it would be undesirable to recommend a fourth dose to all HCWs in South Korea.

This study has several limitations: 1) the study was conducted with a relatively small number of participants from a single institution, 2) each patient’s immunity was not comprehensively examined, and only humoral immunity was assessed due to cost and facility constraints, 3) the study did not consider subvariants of omicron as potential causes of secondary resurgence, and 4) neutralizing antibody titers were not directly measured, and sVNT inhibition score was utilized as an alternative. Despite these limitations, the present study addresses a timely and practical question about the necessity of a fourth booster vaccination for South Korean HCWs.

The sVNT inhibition (%) scores remained high until 8 months for subjects who had COVID-19 infection after completing a third dose, so a fourth vaccination for HCWs with hybrid immunity may not be prioritized over the general population. In order to cope with rapidly changing mutations, additional research on hybrid immunity as well as the development of customized vaccines will be needed.