Do previously infected people still benefit from vaccination against COVID-19?

In a recent study published in PLOS medicine, researchers determined the vaccine effectiveness (VE) of the primary vaccination course for coronavirus disease 2019 (COVID-19). They determined VE against reinfection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19-related hospitalization and mortality. In this way, the researchers assessed the effect of time since vaccination during the predominant eras of different SARS-CoV-2 variants, namely Alpha, Delta and Omicron.

Study: Vaccine effectiveness against SARS-CoV-2 reinfection during periods of Alpha, Delta or Omicron dominance: a Danish nationwide study. Image credit: LookerStudio/Shutterstock


In Denmark, the government is providing free COVID-19 tests, vaccines and medical care to all its residents. They rolled out the COVID-19 vaccination program in December 2020, prioritizing the elderly and those at high risk of serious illness. Likewise, in September 2021, they started a booster vaccination program.

Scientific data indicate reduced effectiveness of COVID-19 vaccines against the Omicron variant (B.1.1.529). Studies have also shown that natural immunity protects against reinfection with SARS-CoV-2 more effectively than vaccination. Thus, it is in the interest of public health to explore the additional benefits of vaccination (if any) in individuals previously infected with SARS-CoV-2.

About the study

In the current study, researchers collected data from four national sources, the Danish Citizen Registration System (CRS), the Danish Microbiology Database (MiBa), the Danish Vaccination Registry (DVR), and the Danish National Patient Registry (DNPR).

Combined with a Danish citizen’s unique personal registration number, this data helped them identify people with a confirmed SARS-CoV-2 infection between January 1, 2020 and January 31, 2022. Similarly, they obtained the periods of dominance of each SARS-CoV-2 variant using CSR data, defined as the period during which a variant accounted for 75% or more of all reverse transcription polymerase chain reaction (RT-PCR) tests of the full genome. In addition, the team examined COVID-19-related hospitalization up to 14 days after or 48 hours before reinfection with SARS-CoV-2 and death within 30 days of reinfection.

In statistical analyses, they included gender, comorbidity and country of origin as categorical variables, while age and length of hospital stay as time-varying covariates. The team used a quasi-Poisson regression model to estimate raw incidence rate ratios (IRRs) and a Cox proportional hazards regression model to estimate hazard ratios (HRs), adjusted for all variables before and in the respective periods after vaccination. Finally, they calculated VE of crude oil (VErough) and modified (VEadjusted) as a percentage using IRR and HR values.

Research findings

The study population consisted of 209,814, 292,978, and 245,530 individuals infected before or during the Alpha, Delta, and Omicron dominance periods, respectively. Of these, 19.2%, 64.9%, and 64.6% of people had received their primary COVID-19 vaccination during the Alpha, Delta, and Omicron periods, respectively. The primary study finding was that previously infected individuals also benefited from COVID-19 vaccination during all three variant periods, data critical to inform policy makers when planning future vaccination strategies.

In the Alpha-dominated period, VE was not statistically significant. It peaked at 71% at 104 days or more after vaccination with any COVID-19 vaccine type. However, the VE against re-infection was highest between 14 and 43 days after the primary vaccination course in the Delta (94%) and Omicron (60%) periods. Although lower than other variants, the researchers recorded an initial VE of 60% against reinfections, even during the Omicron period. These results are consistent with the findings of a study in Qatar that showed a VE of 55.1% against re-infection with Omicron after two doses of a COVID-19 mRNA vaccine.

As older and more vulnerable people received SARS-CoV-2 vaccination with priority. These subjects developed a slower immune response after vaccination, which explains why the observed VE was statistically insignificant during the Alpha period. In addition, all individuals aged 65 or older experienced more severe outcomes than re-infections with SARS-CoV-2 in other age groups, overall and within the same variant period.

Another intriguing finding was that the risk of COVID-19-related hospitalization during the Alpha period was higher for vaccinated versus unvaccinated individuals (IR: 0.002 versus 0.001). Perhaps even before the vaccine rollout, several residents of long-term care facilities (LTCF) had already contracted SARS-CoV-2 infections. Because there were too few hospitalizations and deaths from COVID-19-induced complications in the current study, the researchers were unable to estimate VE for this.

The completeness of the Danish registry data has probably removed any unmeasured biases that might have influenced the research results. However, studies with longer follow-up times were able to identify VE against severe COVID-19 outcomes in people with previous infection.

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