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Comparing SARS-CoV-2 Natural Immunity to Vaccine-Induced Immunity: Reinfections versus Breakthrough Infections

Our take —

This study from Israel, available as a preprint and thus not yet peer reviewed, found that the rates of SARS-CoV-2 breakthrough infections in vaccinated individuals, while very low (highest rate = 1.5%), were significantly higher than the rates of reinfection and hospitalization in previously infected individuals. In addition, individuals who were previously infected who received one dose of the Pfizer vaccine were even more protected from breakthrough infection than the naturally infected group. There were no deaths in any of the groups examined. Given that previously infected individuals may have had multiple infections prior to the study period, the overall applicability of the study to all populations needs more clarification. Lastly, these findings should not be taken as an endorsement that getting infected is a better overall option for protection than the highly effective vaccines that are available as only those who survived initial infection were eligible for analysis.

Study design

Retrospective Cohort

Study population and setting

This study compared the frequency of confirmed SARS-CoV-2 infections, COVID-19 disease, hospitalizations and deaths between individuals with three types of immunity: 1) SARS-CoV-2 naïve individuals who received two doses of the Pfizer vaccine by February 28, 2021 (vaccinated group); 2) people with RT-PCR confirmed SARS-CoV-2 infection prior to February 28, 2021 that had not been vaccinated at all by August 14 (natural immunity group); and 3) previously infected people who received one dose of Pfizer vaccine by May 25, 2021 (7 days before the study period began; infection-vaccine group). Data on outcomes were provided from June 1, 2021 to August 14, 2021 from the Maccabi Healthcare Services (MHS) database, Israel’s second largest Health Maintenance Organization that represents 26% of the population of Israel. The authors used three models to compare the groups while matching individuals from each group 1:1 on age, sex, and socioeconomic status. Model 1 only included people in the natural immunity group with confirmed infection who were matched in time to when vaccines were administered in the vaccine group. Model 2 compared the natural immunity and vaccination groups, but did not match on time of previous infection and vaccination. Model 3 compared the natural infection and infection-vaccine groups. All models were adjusted to account for possible confounders. During the time period examined for breakthrough and re-infections Israel was experiencing a surge in Delta variant related infections.

Summary of Main Findings

Overall, infections were very rare in all of the groups studied, and only 1.5% or less of study participants were infected in any of the analysis groups, regardless of how immunity was derived; there were no deaths in any group.

Model 1 compared 16,215 people in both the vaccinated and natural immunity groups and found that cases in the vaccinated group (n=238, 1.5%) were 13 fold more likely to experience a breakthrough infection than the natural immunity group (n=19, 0.12%). The majority of the cases were symptomatic. There were very few hospitalizations in either group with only 8 in the vaccine arm and 1 in the natural immunity arm.

Model 2 compared 46,035 people in both the vaccinated and natural immunity groups, and found that cases in the vaccinated group (n=640, 1.4%) were 6-fold more likely to experience a breakthrough infection than the natural immunity group (n=108, 0.23%). The majority of the cases were symptomatic. There were very few hospitalizations in either group with only 21 in the vaccine arm and 4 in the natural immunity arm.

Model 3 compared 14,029 people in both the natural immunity and infection-vaccine groups and found that cases in the infection-vaccine group (n=20, 0.14%) had about half the risk of experiencing a breakthrough infection than the natural immunity group (n=37, 0.26%). There was one hospitalization in the natural immunity group.

Study Strengths

Israel has a relatively high rate of COVID vaccination, and the nationalized healthcare database used represents an extremely large portion of the population. Limiting previous infections and vaccinations to only those which occurred by February 28 decreased the risk of continued viral shedding from the previously infected individuals, thereby ensuring that they are reporting true re-infections. The study was large and attempted to control for other factors that may affect COVID reporting in these individuals through a matched design.

Limitations

As the authors state the primary SARS-CoV-2 variant in Israel at this time was Delta, and therefore these results may not hold for other variants. In addition, Israel only used the Pfizer mRNA vaccine, so these results may not be applicable to other vaccine platforms. One important limitation of this study, that the authors do not address, is that it is possible that some of the previously infected individuals could have had multiple SARS-CoV-2 infections before their Feb 28 cut-off. It would be more applicable to treat anyone with multiple infections as a separate group or remove them from analysis. Lastly, more granular detail on the data used would be helpful to fully assess these findings.

Value added

This is one of the first studies to directly compare the protection against infection conferred through previous SARS-CoV-2 infection, vaccination, and a combination of both, in a large population with significant vaccine roll-out.

This review was posted on: 10 September 2021