Do two or more mRNA vaccine doses provide additional protection in patients with prior COVID-19 infection?

By Neha MathurReviewed by Danielle Ellis, B.Sc.Mar 30 2023

In a recent article published in the Open Forum Infectious Diseases, researchers conducted a retrospective cohort study among vaccinated and unvaccinated coronavirus disease 2019 (COVID-19) patients between December 16, 2020, and March 15, 2022, in the United States of America (USA).

Background

Several studies have assessed the protective immunity elicited due to prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but did not address the role of vaccination in individuals with natural immunity. Although many researchers pursued evidence of the additional benefits of COVID-19 vaccination, if any, data on the protective efficacy of prior COVID-19 with or without vaccination is still scarce.

Thus, it remains unknown whether a prior SARS-CoV-2 infection provides similar immune protection as two doses of a messenger ribonucleic acid (mRNA) vaccine.

About the study

In the present study, researchers investigated the risk of COVID-19 in vaccinated and unvaccinated individuals with and without prior infection. They depicted the frequency of COVID-19 across all study groups using a Simon-Makuch hazard plot. Likewise, they used multivariable Cox proportional hazards regression to assess the correlation of patient demographics and prior infection & vaccination status with new reinfections.

Previous observational studies performed in large cohorts have established that the absolute risk of reinfection within six to 12 months, i.e., early after the initial illness, is low; however, vaccination extends it further to >12 months after the initial infection by boosting the waning immunity. Given the lack of a correlate of protection (CoP) and its waning, determination of the precise time for a vaccine dose post-recent infection is challenging.

So, the researchers did not focus on determining the time from prior infection to vaccination and its possible effect(s) on protective immunity against reinfection.

Results

The study comprised 101,941 subjects, of which 55% were female, and  5,957 individuals had suffered at least once from COVID-19, with the average time between infection and the beginning of the study being 40 days. In total, 71% of the study population received an mRNA COVID-19 vaccine, either BNT162b2 or mRNA-1273, by the end of the study. All study participants had comparable socio-economic demographics.

The authors noted that subjects who had a prior infection and received an mRNA COVID-19 vaccination exhibited the lowest aggregate incidence of COVID-19 throughout the study. Overall COVID-19 rates remained low in all groups before the Omicron wave, except in the group with individuals having no prior infection or vaccination history.

In the period before the advent of SARS-CoV-2’s most lethal variant of concern (VOC), i.e., the Delta VOC, individuals with hybrid immunity due to vaccination and previous infection lowered the cumulative incidence of COVID-19 than infection alone. Importantly, it suggested the immune protection conferred by ancestral strain-based vaccines was robust against pre-Delta variants.

Omicron VOC was predominant worldwide in early 2022. Studies showed that boosting patients with prior COVID-19 provided additional immune protection against severe disease at 39.3% vaccine effectiveness (VE).

During the late Delta-early Omciron phase, subjects with a prior infection who were vaccinated remained most protected against reinfections. Even during the Omicron-predominant era, cumulative infection rates remained lowermost in those with hybrid immunity due to prior infection and consequent vaccination.

As cumulative infection rates for unvaccinated vs. vaccinated people became almost comparable during the Omicron phase, it raised the question of whether vaccination provided any additional benefit. However, even during the Omicron wave, vaccination in those with prior COVID-19 conferred a significant protective immunity compared to those previously infected but not vaccinated (HR 0.64 vs. 0.74).

The decline in the cumulative infection risk from Delta or Omicron VOCs post-receiving ≥2 doses of the mRNA vaccines in a previously infected cohort was notable. The people comprising this cohort had COVID-19 before December 16, 2020, i.e., in the pre-Delta phase.

Despite a surge in COVID-19 cases in all groups during the Omicron wave, the inter-group difference in cumulative incidence persisted. Vaccination and prior SARS-CoV-2 infection showed independent correlations with lower infection rates throughout the study, and it was robust during the pre-Omicron phase. Also, age and gender did not modify the observed association.

Conclusions

Similar to several previous studies, this study favored the current recommendation for post-infection COVID-19 vaccination and evidenced that the vaccines based on ancestral SARS-CoV-2 strain boosted against Omicron even in individuals infected long ago (remote infections) from ancestral or other SARS-CoV-2 VOCs.

A vaccine well-aligned to the predominant SARS-CoV-2 VOC was anticipated to confer substantial additional protection even in people who contracted the disease long ago. So, the study findings also favor the recommendations for bivalent vaccines based on ancestral strain and Omicron BA.4/BA.5.

Though tedious to quantify and estimate, several studies suggested that T-cell-mediated immunity might also provide long-term protective immunity in individuals whose immunity waned after six to 14 months of infection.

Thus, amid the continuous emergence of Omicron subvariants, e.g., XBB.1.5, it is of utmost significance to continuously evaluate the duration of protective immunity conferred by a bivalent mRNA COVID-19 vaccine (booster), especially in individuals with remote infections due to ancestral or other SARS-CoV-2 pre-Delta VOCs. Likewise, future studies would have to evaluate the effect of future SARS-CoV-2 VOC-specific boosters.

Nevertheless, the study results demonstrated a significant correlation between COVID-19 vaccination and lowered risk of a COVID-19 reinfection even in those with prior infection, albeit illness itself conferred robust protection against reinfection for several months.

The researchers advocated vaccinating individuals with prior infection to boost their natural protective immunity against emerging variants sharing protective epitopes with the vaccine used, e.g., bivalent vaccines.