Our study showed that receipt of the BNT162b2 vaccine in patients who had recovered from Covid-19 was associated with substantially lower reinfection rates. These results are consistent with data from studies that have shown strong immunologic responses to vaccination in previously infected persons.11.19
Although vaccine effectiveness was lower among patients who were 65 years of age or older than among younger patients, the vaccine still offered substantial protection among older patients. However, among the unvaccinated patients, the reinfection rate among the older patients was much lower than that among the younger patients (3.02 cases per 100,000 persons per day vs. 10.79 cases per 100,000 persons per day). This observation may be explained if we assume that older patients who had already been infected with SARS-CoV-2 would have observed enhanced social distancing and other required precautions, especially during the surge of the delta variant, even if they had decided against vaccination. Therefore, the differences in reinfection rates between vaccinated and unvaccinated older patients were lower than those in the younger population.
In the secondary analysis, we found that the receipt of more than one vaccine dose was not associated with greater effectiveness. However, it should be noted that only 19% of the vaccinated patients received more than one vaccine dose during the study period. Given the previous exposure to the virus, it seems that the primary vaccine dose in recovered patients provided a more robust and longer immunogenic response than the first dose alone in patients without previous Covid-19. These results are in concordance with the findings from a previous study conducted in Italy.11
Since March 2021, the Israeli Ministry of Health has recommended the administration of a single dose of vaccine in patients who have recovered from Covid-19, with the dose to be administered 3 months after recovery from the primary infection. However, not all patients who were eligible to receive this dose hurried to receive a postrecovery vaccine. Soon after Covid-19 vaccines had become available, Israel established an immunity passport policy, also known as the Green Pass, with the primary objective of allowing safe relaxation of Covid-19 restrictions.20 Initially, the Ministry of Health issued a Green Pass to all patients who had recovered from Covid-19 without any restriction. However, in October 2021, because of the surge in the delta variant, the Ministry of Health decided that patients who had not been vaccinated by 6 months after recovery would not be entitled to a Green Pass.21
In Israel, the receipt of a Covid-19 vaccine is a personal choice. Vaccine hesitancy after recovery from Covid-19 might have stemmed from personal safety concerns in patients who wanted to ensure that the vaccine was safe and beneficial for them. On the other hand, some patients who had a history of severe symptoms during their illness might have been willing to do anything that would avoid reinfection and therefore had a greater incentive to get the vaccine.
Our study has several strengths. First, the results are based on the integrated medical record system of Clalit Health Services, with detailed demographic, clinical, and laboratory testing data, including all dates and results of RT-qPCR testing, updated daily with information from the Ministry of Health data warehouse . Second, the large cohort is available for analysis with a relatively long-term follow-up. Third, the study period included the entire surge of the delta variant in Israel, during which the incidence of Covid-19 was one of the highest in the world.22 Thus, the number of reinfections was sufficient to show vaccine effectiveness.
Our study also has several limitations. As in any real-world observational study, the patients were not randomly assigned to receive or not to receive the vaccine. Much confounding is expected to arise from a lack of randomization because of substantial dissimilarities in the clinical backgrounds and sociodemographic characteristics of the two groups. This limitation is inherent in every real-world, population-based study of vaccine effectiveness, since the patients who received a vaccine may differ from those who did not.8.23 We attempted to overcome such bias by adjusting for variables known to affect rates of Covid-19 complications. However, measurement or correction may not have been performed adequately for unobserved or unmeasured sources of bias.
Another possible source of bias is the variation of exposure to SARS-CoV-2 during the study period. To minimize this potential bias, we entered patients in the study only until May 31, 2021, before the start of the surge in the delta variant. Therefore, we assumed that after adjustment for all covariates, the possible exposure variation had a similar effect in the vaccinated and unvaccinated groups.
A further limitation of this study is that reinfections were identified on the basis of a positive result on RT-qPCR assay, a procedure that would miss patients who were reinfected but were unaware of their infection or those who decided to avoid RT-qPCR testing, which would be more likely in mild cases. If we assume that infection was more likely to be asymptomatic or only mildly symptomatic in those who had been vaccinated, testing might have been less likely in this group. Thus, many records of infection may have been missed — a factor that could have substantially skewed reinfection rates in the vaccinated group and resulted in an overestimation of vaccine effectiveness. Therefore, we compared the overall testing rate in the two groups and found that testing was more frequent in the vaccinated group (Table S4).
An additional limitation is that we did not assess data on the severity of infection or on hospitalization or death in the reinfected patients since those outcomes were outside the scope of the study. However, in a recent study involving a large national cohort in Qatar, the risk that reinfection would result in hospitalization or death was 90% lower than the risk associated with primary infection.24
Finally, our findings were limited to the BNT162b2 vaccine. Although a recently published study provided evidence that the mRNA-1273 vaccine is slightly more effective than the BNT162b2 vaccine in participants who had received two vaccine doses,25.26 we cannot deduce whether this observation is relevant in averting reinfection with respect to patients who have recovered from Covid-19. Despite these limitations, we believe that our results may provide meaningful answers to a crucial question regarding vaccination policy with respect to patients after recovery from Covid-19.
Our study showed that among patients who had recovered from Covid-19, the receipt of one dose of the BNT162b2 vaccine was associated with an 82% lower risk of recurrent SARS-CoV-2 infection among those between 16 and 64 years of age and a 60% lower risk among those 65 years of age or older. No substantial difference was found in reinfection risk for two doses of vaccine as compared with one dose. The evidence that was gathered in this study during a surge of the delta variant in Israel supports a public health policy of vaccinating patients who have recovered from Covid-19, particularly in places where the delta variant is still of concern.