“Are persons vaccinated after SARS-CoV-2 infection better protected against breakthrough infection than those vaccinated without prior infection?”

With this question in mind, the team of researchers from Qatar undertook a large retrospective cohort study on 1,531,736 individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine between December 21, 2020, and September 19, 2021.

The study, recently published in The Journal of the American Medical Association, deduced that previous SARS-CoV-2 infection is associated with a statistically significant reduced hazard of breakthrough infection among recipients of both the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna) vaccines.

SARS-CoV-2 infection and immunization status in Qatar

Coronavirus disease 19 (COVID-19) vaccination drive began in December 2020 in Qatar, initially with the BNT162b2 (Pfizer-BioNTech) vaccine and, three months later, adding the mRNA-1273 (Moderna) vaccine. Later from January through June 2021, the country experienced two SARS-CoV-2 waves, dominated by the Alpha (B.1.1.7) and Beta (B.1.351) variants.

By the summer of 2021, Delta had become the dominant variant. The team took an opportunity through the whole scenario to assess whether persons vaccinated with a prior SARS-CoV-2 infection had a lower incidence of breakthrough infections than those vaccinated without previous infection.

Study design

Association between prior infection and acquisition of infection after vaccination was investigated using two retrospectively matched-cohort studies. The study leveraged the national, federated databases that captured all SARS-CoV-2–related data, including infection, immunization, and demographic details of pertinent individuals since the start of the epidemic. The eligible study population included a total of 1,531,736 eligible BNT162b2-vaccinated and mRNA-1273–vaccinated individuals in the federated database between December 21, 2020, and September 19, 2021.

The incidence of documented SARS-CoV-2 infection after the second vaccine dose was compared in the cohort of individuals who experienced PCR-confirmed infection before vaccination vs. incidence among those with no record of a prior infection for both the vaccine cohorts. The follow-up lasted from 14 days after the second dose up to the earliest occurrence of either PCR-positive nasopharyngeal swab, all-cause death, or end-of-study censoring (September 19, 2021).

To control for any differences in exposure risk and variant exposure, individuals were exact matched based on prior infection status in a 1:1 ratio by sex, 5-year age group, nationality, and calendar week of first vaccine dose. Cumulative incidence of infection was calculated using the Kaplan-Meier estimator method.

An additional analysis was conducted to assess the association between the timing of boosting natural immunity through vaccination and the incidence of breakthrough infection.

Study findings

The BNT162b2-vaccinated cohort comprised 99,226 individuals with prior infection (PCR-positive nasopharyngeal swab) and 290,432 matched individuals without prior infection. Amongst these, 159 reinfections occurred in those with and 2509 in those without prior infection, 14 days or more after the second dose.

Cumulative infection incidence amongst BNT162b2-vaccinated individuals was an estimated 0.15% (95%CI, 0.12%-0.18%) in those with and 0.83% (95%CI, 0.79%-0.87%) in those without prior infection at 120 days of follow-up. Cumulative infection incidence appeared to accelerate among those without prior infection after the 110^th day of follow-up.

In the case of mRNA-1273-vaccinated, 58,096 individuals with and 169,514 matched individuals without prior PCR-confirmed infection comprised the cohort. Forty-three and 368 reinfections occurred in vaccinated individuals with and without prior infection, respectively. It interpreted into a cumulative infection incidence of an estimated 0.11% (95%CI, 0.08%-0.15%) in those with and 0.35% (95%CI, 0.32%-0.40%) in those without prior infection at 120 days of follow-up. Here, in mRNA-1273-vaccinated individuals, cumulative infection incidence appeared to accelerate among vaccinated individuals without prior infection after the 80^th day of follow-up.

The study also found that vaccinated individuals who had a prior SARS-CoV-2 infection 6 months or more before dose 1 were at significantly lower risk for breakthrough infection than those who got infected less than 6 months before the first dose.

Implications

Given the utilization of a large dataset, the study establishes its reliability for implications over a wider population across the globe.

“Prior infection among those vaccinated—a hybrid of natural and vaccine immunity—appeared to be associated with additional reduction in breakthrough infection,” the team concludes.

Incidence of breakthrough infection accelerates with time after the second dose among those with no prior infection, suggesting waning of vaccine-induced immunity over time.

Evidence suggests that the mRNA-1273 vaccine protects better than the BNT162b2. Nevertheless, the team speculates that the observed differences in breakthrough infection incidence in vaccinated individuals could be attributable to – an additional one-week interval between two doses of mRNA-1273 (a longer dose interval might be associated with an improved immunity) and a larger vaccine dose of mRNA-1273.

Written by

Namita Mitra

After earning a bachelor’s degree in Veterinary Sciences and Animal Health  (BVSc) in 2013, Namita went on to pursue a Master of Veterinary Microbiology from GADVASU, India. Her Master’s research on the molecular and histopathological diagnosis of avian oncogenic viruses in poultry brought her two national awards. In 2013, she was conferred a doctoral degree in Animal Biotechnology that concluded with her research findings on expression profiling of apoptosis-associated genes in canine mammary tumors. Right after her graduation, Namita worked as Assistant Professor of Animal Biotechnology and taught the courses of Animal Cell Culture, Animal Genetic Engineering, and Molecular Immunology.