2021 08 24 21262415v1 Full

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Title page
Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity:

reinfections versus breakthrough infections
Sivan Gazit, MD MA1,2*; Roei Shlezinger, BA1; Galit Perez, MN MA2; Roni Lotan,
PhD2; Asaf Peretz, MD1,3; Amir Ben-Tov, MD1,4; Dani Cohen, PhD4; Khitam
Muhsen, PhD4; Gabriel Chodick, PhD MHA2,4; Tal Patalon, MD1,2
*Corresponding author.
1
Kahn Sagol Maccabi (KSM) Research & Innovation Center, Maccabi Healthcare
Services, Tel Aviv, 68125, Israel.
2
Maccabitech Institute for Research and Innovation, Maccabi Healthcare Services,
Israel.
3
Internal Medicine COVID-19 Ward, Samson Assuta Ashdod University Hospital,
Ashdod Israel.
4
Sackler Faculty of Medicine, School of Public Health, Tel Aviv University, Tel
Aviv, Israel.
The authors declare they have no conflict of interest.
Funding: There was no external funding for the project.
Corresponding author: Sivan Gazit, gazit_s@mac.org.il, 27 HaMared street, Tel Aviv,

68125, Israel
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2021.08.24.21262415; this version posted August 25, 2021. The copyright holder for this preprint
Abstract
Background:
Reports of waning vaccine-induced immunity against COVID-19 have begun to
surface. With that, the comparable long-term protection conferred by previous
infection with SARS-CoV-2 remains unclear.
Methods:
We conducted a retrospective observational study comparing three groups: (1)SARS-
CoV-2-naïve individuals who received a two-dose regimen of the BioNTech/Pfizer
mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been
vaccinated, and (3)previously infected and single dose vaccinated individuals. Three
multivariate logistic regression models were applied. In all models we evaluated four
outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related
hospitalization and death. The follow-up period of June 1 to August 14, 2021, when
the Delta variant was dominant in Israel.
Results:
SARS-CoV-2-naïve vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk
for breakthrough infection with the Delta variant compared to those previously
infected, when the first event (infection or vaccination) occurred during January and
February of 2021. The increased risk was significant (P<0.001) for symptomatic
disease as well. When allowing the infection to occur at any time before vaccination
(from March 2020 to February 2021), evidence of waning natural immunity was
demonstrated, though SARS-CoV-2 naïve vaccinees had a 5.96-fold (95% CI, 4.85 to
7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21)
increased risk for symptomatic disease. SARS-CoV-2-naïve vaccinees were also at a
greater risk for COVID-19-related-hospitalizations compared to those that were
previously infected.
Conclusions:
This study demonstrated that natural immunity confers longer lasting and stronger
protection against infection, symptomatic disease and hospitalization caused by the
Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced
immunity. Individuals who were both previously infected with SARS-CoV-2 and
given a single dose of the vaccine gained additional protection against the Delta
variant.
Introduction
The heavy toll that SARS-CoV-2 infection has been taking on global health and
healthcare resources has created an urgent need to estimate which part of the
population is protected against COVID-19 at a given time in order to set healthcare
policies such as lockdowns and to assess the possibility of herd immunity.
To date, there is still no evidence-based, long-term correlate of protection1. This lack
of correlate of protection has led to different approaches in terms of vaccine resource
allocation, namely the need for vaccine administration in recovered patients, the need
for booster shots in previously vaccinated individuals or the need to vaccinate low-
risk populations, potentially previously exposed.
The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer
BNT162b2 mRNA COVID-19 vaccine was demonstrated in clinical trials 2 and in
observational settings3,4. However, long term effectiveness across different variants is
still unknown, though reports of waning immunity are beginning to surface, not
merely in terms of antibody dynamics over time5–7, but in real-world settings as well8.
Alongside the question of long-term protection provided by the vaccine, the degree
and duration to which previous infection with SARS-CoV-2 affords protection against
repeated infection also remains unclear. Apart from the paucity of studies examining
long-term protection against reinfection9, there is a challenge in defining reinfection
as opposed to prolonged viral shedding10. While clear-cut cases exist, namely two
separate clinical events with two distinct sequenced viruses, relying solely on these
cases will likely result in an under-estimation of the incidence of reinfection.
Different criteria based on more widely-available information have been suggested11,
the Centers for Disease Control and Prevention’s (CDC) guidelines refer to two
positive SARS-CoV-2 polymerase chain reaction (PCR) test results at least 90 days
apart.12 Using similar criteria, population-based studies demonstrated natural
immunity13,14 with no signs of waning immunity for at least 7 months, though
protection was lower for those aged 65 or older9.
The Delta (B.1.617.2) Variant of Concern (VOC), initially identified in India and
today globally prevalent, has been the dominant strain in Israel since June 2021. The
recent surge of cases in Israel15, one of the first countries to embark on a nationwide
vaccination campaign (mostly with the BioNTech/Pfizer BNT162b2 vaccine), has
raised concerns about vaccine effectiveness against the Delta variant, including
official reports of decreased protection16. Concomitantly, studies have demonstrated
only mild differences in short-term vaccine effectiveness17 against the Delta variant,
as well as substantial antibody response18. Apart from the variant, the new surge was
also explained by the correlation found between time-from-vaccine and breakthrough
infection rates, as early vaccinees were demonstrated to be significantly more at risk
than late vaccinees8. Now, when sufficient time has passed since both the beginning
of the pandemic and the deployment of the vaccine, we can examine the long-term
protection of natural immunity compared to vaccine-induced immunity.
To this end, we compared the incidence rates of breakthrough infections to the
incidence rates of reinfection, leveraging the centralized computerized database of
Maccabi Healthcare Services (MHS), Israel's second largest Health Maintenance
Organization.
Methods
Study design and population
A retrospective cohort study was conducted, leveraging data from MHS’ centralized
computerized database. The study population included MHS members aged 16 or
older who were vaccinated prior to February 28, 2021, who had a documented SARS-
CoV-2 infection by February 28, 2021, or who had both a documented SARS-CoV-2
infection by February 28, 2021 and received one dose of the vaccine by May 25,
2021, at least 7 days before the study period. On March 2, 2021, The Israeli Ministry
of Health revised its guidelines and allowed previously SARS-CoV-2 infected
individuals to receive one dose of the vaccine, after a minimum 3-month-interval
from the date of infection
Data Sources
Anonymized Electronic Medical Records (EMRs) were retrieved from MHS’
centralized computerized database for the study period of March 1, 2020 to August
14, 2021.
MHS is a 2.5-million-member, state-mandated, non-for-profit, second largest health
fund in Israel, which covers 26% of the population and provides a representative
sample of the Israeli population. Membership in one of the four national health funds
is mandatory, whereas all citizens must freely choose one of four funds, which are
prohibited by law from denying membership to any resident. MHS has maintained a
centralized database of EMRs for three decades, with less than 1% disengagement
rate among its members, allowing for a comprehensive longitudinal medical follow-
up. The centralized dataset includes extensive demographic data, clinical
measurements, outpatient and hospital diagnoses and procedures, medications

dispensed, imaging performed and comprehensive laboratory data from a single
central laboratory.
Data extraction and definition of the study variables
COVID-19-related data
COVID-19-related information was captured as well, including dates of the first and
second dose of the vaccine and results of any polymerase chain reaction (PCR) tests
for SARS-CoV-2, given that all such tests are recorded centrally. Records of COVID-
19-related hospitalizations were retrieved as well, and COVID-19-related mortality
was screened for. Additionally, information about COVID-19-related symptoms was
extracted from EMRs, where they were recorded by the primary care physician or a
certified nurse who conducted in-person or phone visits with each infected individual.
Exposure variable: study groups
The eligible study population was divided into three groups: (1)fully vaccinated and
SARS-CoV-2-naïve individuals, namely MHS members who received two doses of
the BioNTech/Pfizer mRNA BNT162b2 vaccine by February 28, 2021, did not
receive the third dose by the end of the study period and did not have a positive PCR
test result by June 1, 2021; (2) unvaccinated previously infected individuals, namely
MHS members who had a positive SARS-CoV-2 PCR test recorded by February 28,
2021 and who had not been vaccinated by the end of the study period; (3) previously
infected and vaccinated individuals, including individuals who had a positive SARS-
CoV-2 PCR test by February 28, 2021 and received one dose of the vaccine by May
25, 2021, at least 7 days before the study period. The fully vaccinated group was the
comparison (reference) group in our study. Groups 2 and 3, were matched to the
comparison group 1 in a 1:1 ratio based on age, sex and residential socioeconomic
status.
Dependent variables
We evaluated four SARS-CoV-2-related outcomes, or second events: documented
RT-PCR confirmed SARS-CoV-2 infection, COVID-19, COVID-19-related
hospitalization and death. Outcomes were evaluated during the follow-up period of
June 1 to August 14, 2021, the date of analysis, corresponding to the time in which
the Delta variant became dominant in Israel.
Covariates
Individual-level data of the study population included patient demographics, namely
age, sex, socioeconomic status (SES) and a coded geographical statistical area (GSA,
assigned by Israel’s National Bureau of Statistics, corresponds to neighborhoods and
is the smallest geostatistical unit of the Israeli census). The SES is measured on a
scale from 1 (lowest) to 10, and the index is based on several parameters, including
household income, educational qualifications, household crowding and car ownership.
Data were also collected on last documented body mass index (BMI) and information
about chronic diseases from MHS’ automated registries, including cardiovascular
diseases19, hypertension20, diabetes21, chronic kidney disease22, chronic obstructive
pulmonary disease, immunocompromised conditions, and cancer from the National
Cancer Registry23.
Statistical analysis
Two multivariate logistic regression models were applied that evaluated the four
aforementioned SARS-CoV-2-related outcomes as dependent variables, while the
study groups were the main independent variables.
Model 1– previously infected vs. vaccinated individuals, with matching for time of
first event
In model 1, we examined natural immunity and vaccine-induced immunity by
comparing the likelihood of SARS-CoV-2-related outcomes between previously
infected individuals who have never been vaccinated and fully vaccinated SARS-
CoV-2-naïve individuals. These groups were matched in a 1:1 ratio by age, sex, GSA
and time of first event. The first event (the preliminary exposure) was either the time
of administration of the second dose of the vaccine or the time of documented
infection with SARS-CoV-2 (a positive RT-PCR test result), both occurring between
January 1, 2021 and February 28, 2021. Thereby, we matched the “immune
activation” time of both groups, examining the long-term protection conferred when
vaccination or infection occurred within the same time period. The three-month
interval between the first event and the second event was implemented in order to
capture reinfections (as opposed to prolonged viral shedding) by following the 90-day
guideline of the CDC.
Model 2
In model 2, we compared the SARS-CoV-2 naïve vaccinees to unvaccinated
previously infected individuals while intentionally not matching the time of the first
event (i.e., either vaccination or infection), in order to compare vaccine-induced
immunity to natural immunity, regardless of time of infection. Therefore, matching

was done in a 1:1 ratio based on age, sex and GSA alone. Similar to the model 1,
either event (vaccination or infection) had to occur by February 28, to allow for the
90-day interval. The four SARS-CoV-2 study outcomes were the same for this model,
evaluated during the same follow-up period.
Model 3
Model 3 examined previously infected individuals vs. previously-infected-and-once-
vaccinated individuals, using “natural immunity” as the baseline group. We matched
the groups in a 1:1 ratio based on age, sex and GSA. SARS-CoV-2 outcomes were the
same, evaluated during the same follow-up period.
In all three models, we estimated natural immunity vs. vaccine-induced immunity for
each SARS-CoV-2-related outcome, by applying logistic regression to calculate the
odds ratio (OR) between the two groups in each model, with associated 95%
confidence intervals (CIs). Results were then adjusted for underlying comorbidities,
including obesity, cardiovascular diseases, diabetes, hypertension, chronic kidney
disease, cancer and immunosuppression conditions.
Analyses were performed using Python version 3.73 with the stats model package.
P < 0.05 was considered statistically significant.
Ethics declaration
This study was approved by the MHS (Maccabi Healthcare Services) Institutional
Review Board (IRB). Due to the retrospective design of the study, informed consent
was waived by the IRB, and all identifying details of the participants were removed
before computational analysis.

Data availability statement
According to the Israel Ministry of Health regulations, individual-level data cannot be
shared openly. Specific requests for remote access to de-identified community-level
data should be directed to KSM, Maccabi Healthcare Services Research and
Innovation Center.
Code availability
Specific requests for remote access to the code used for data analysis should be
referred to KSM, Maccabi Healthcare Services Research and Innovation Center.

Results
Overall, 673,676 MHS members 16 years and older were eligible for the study group
of fully vaccinated SARS-CoV-2-naïve individuals; 62,883 were eligible for the study
group of unvaccinated previously infected individuals and 42,099 individuals were
eligible for the study group of previously infected and single-dose vaccinees.
Model 1 – previously infected vs. vaccinated individuals, with matching for time of
first event
In model 1, we matched 16,215 persons in each group. Overall, demographic
characteristics were similar between the groups, with some differences in their
comorbidity profile (Table 1a).
During the follow-up period, 257 cases of SARS-CoV-2 infection were recorded, of
which 238 occurred in the vaccinated group (breakthrough infections) and 19 in the
previously infected group (reinfections). After adjusting for comorbidities, we found a
statistically significant 13.06-fold (95% CI, 8.08 to 21.11) increased risk for
breakthrough infection as opposed to reinfection (P<0.001). Apart from age ≥60
years, there was no statistical evidence that any of the assessed comorbidities
significantly affected the risk of an infection during the follow-up period (Table 2a).
As for symptomatic SARS-COV-2 infections during the follow-up period, 199 cases
were recorded, 191 of which were in the vaccinated group and 8 in the previously
infected group. Symptoms for all analyses were recorded in the central database
within 5 days of the positive RT-PCR test for 90% of the patients, and included
chiefly fever, cough, breathing difficulties, diarrhea, loss of taste or smell, myalgia,
weakness, headache and sore throat. After adjusting for comorbidities, we found a
27.02-fold risk (95% CI, 12.7 to 57.5) for symptomatic breakthrough infection as
opposed to symptomatic reinfection (P<0.001) (Table 2b). None of the covariates
were significant, except for age ≥60 years.
Nine cases of COVID-19-related hospitalizations were recorded, 8 of which were in
the vaccinated group and 1 in the previously infected group (Table S1). No COVID-
19-related deaths were recorded in our cohorts.
Model 2 –previously infected vs. vaccinated individuals, without matching for time
of first event
In model 2, we matched 46,035 persons in each of the groups (previously infected vs.
vaccinated). Baseline characteristics of the groups are presented in Table 1a. Figure 1
demonstrates the timely distribution of the first infection in reinfected individuals.
When comparing the vaccinated individuals to those previously infected at any time
(including during 2020), we found that throughout the follow-up period, 748 cases of
SARS-CoV-2 infection were recorded, 640 of which were in the vaccinated group
(breakthrough infections) and 108 in the previously infected group (reinfections).
After adjusting for comorbidities, a 5.96-fold increased risk (95% CI, 4.85 to 7.33)
increased risk for breakthrough infection as opposed to reinfection could be observed
(P<0.001) (Table 3a). Apart from SES level and age ≥60, that remained significant in
this model as well, there was no statistical evidence that any of the comorbidities
significantly affected the risk of an infection.
Overall, 552 symptomatic cases of SARS-CoV-2 were recorded, 484 in the
vaccinated group and 68 in the previously infected group. There was a 7.13-fold (95%
CI, 5.51 to 9.21) increased risk for symptomatic breakthrough infection than
symptomatic reinfection (Table 3b). COVID-19 related hospitalizations occurred in 4
and 21 of the reinfection and breakthrough infection groups, respectively. Vaccinated

individuals had a 6.7-fold (95% CI, 1.99 to 22.56) increased to be admitted compared
to recovered individuals. Being 60 years of age or older significantly increased the
risk of COVID-19-related hospitalizations (Table S2). No COVID-19-related deaths
were recorded.
Model 3 - previously infected vs. vaccinated and previously infected individuals
In model 3, we matched 14,029 persons. Baseline characteristics of the groups are
presented in Table 1b. Examining previously infected individuals to those who were
both previously infected and received a single dose of the vaccine, we found that the
latter group had a significant 0.53-fold (95% CI, 0.3 to 0.92) (Table 4a) decreased risk
for reinfection, as 20 had a positive RT-PCR test, compared to 37 in the previously
infected and unvaccinated group. Symptomatic disease was present in 16 single dose
vaccinees and in 23 of their unvaccinated counterparts. One COVID-19-related
hospitalization occurred in the unvaccinated previously infected group. No COVID-
19-related mortality was recorded.
We conducted a further sub-analysis, compelling the single-dose vaccine to be
administered after the positive RT-PCR test. This subset represented 81% of the
previously-infected-and-vaccinated study group. When performing this analysis, we
found a similar, though not significant, trend of decreased risk of reinfection, with an
OR of 0.68 (95% CI, 0.38 to 1.21, P-value=0.188).

Discussion
This is the largest real-world observational study comparing natural immunity, gained
through previous SARS-CoV-2 infection, to vaccine-induced immunity, afforded by
the BNT162b2 mRNA vaccine. Our large cohort, enabled by Israel’s rapid rollout of
the mass-vaccination campaign, allowed us to investigate the risk for additional
infection – either a breakthrough infection in vaccinated individuals or reinfection in
previously infected ones – over a longer period than thus far described.
Our analysis demonstrates that SARS-CoV-2-naïve vaccinees had a 13.06-fold
increased risk for breakthrough infection with the Delta variant compared to those
previously infected, when the first event (infection or vaccination) occurred during
January and February of 2021. The increased risk was significant for a symptomatic
disease as well.
Broadening the research question to examine the extent of the phenomenon, we
allowed the infection to occur at any time between March 2020 to February 2021
(when different variants were dominant in Israel), compared to vaccination only in
January and February 2021. Although the results could suggest waning natural
immunity against the Delta variant, those vaccinated are still at a 5.96-fold increased
risk for breakthrough infection and at a 7.13-fold increased risk for symptomatic
disease compared to those previously infected. SARS-CoV-2-naïve vaccinees were
also at a greater risk for COVID-19-related-hospitalization compared to those who
were previously infected.
Individuals who were previously infected with SARS-CoV-2 seem to gain additional
protection from a subsequent single-dose vaccine regimen. Though this finding
corresponds to previous reports24,25, we could not demonstrate significance in our
cohort.
The advantageous protection afforded by natural immunity that this analysis
demonstrates could be explained by the more extensive immune response to the
SARS-CoV-2 proteins than that generated by the anti-spike protein immune activation
conferred by the vaccine26,27. However, as a correlate of protection is yet to be
proven1,28, including the role of B-Cell29 and T-cell immunity30,31, this remains a
hypothesis.
Our study has several limitations. First, as the Delta variant was the dominant strain in
Israel during the outcome period, the decreased long-term protection of the vaccine
compared to that afforded by previous infection cannot be ascertained against other
strains. Second, our analysis addressed protection afforded solely by the
BioNTech/Pfizer mRNA BNT162b2 vaccine, and therefore does not address other
vaccines or long-term protection following a third dose, of which the deployment is
underway in Israel. Additionally, as this is an observational real-world study, where
PCR screening was not performed by protocol, we might be underestimating
asymptomatic infections, as these individuals often do not get tested.
Lastly, although we controlled for age, sex, and region of residence, our results might
be affected by differences between the groups in terms of health behaviors (such as
social distancing and mask wearing), a possible confounder that was not assessed. As
individuals with chronic illness were primarily vaccinated between December and
February, confounding by indication needs to be considered; however, adjusting for
obesity, cardiovascular disease, diabetes, hypertension, chronic kidney disease,
chronic obstructive pulmonary disease, cancer and immunosuppression had only a
small impact on the estimate of effect as compared to the unadjusted OR. Therefore,
residual confounding by unmeasured factors is unlikely.

This analysis demonstrated that natural immunity affords longer lasting and stronger
protection against infection, symptomatic disease and hospitalization due to the Delta
variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced
immunity. Notably, individuals who were previously infected with SARS-CoV-2 and
given a single dose of the BNT162b2 vaccine gained additional protection against the
Delta variant. The long-term protection provided by a third dose, recently
administered in Israel, is still unknown.

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28. Chia WN, Zhu F, Ong SWX, et al. Dynamics of SARS-CoV-2 neutralising
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Tables and figures
Table 1a. Characteristics of study population, model 1 and 2.
Model 1 – with matching of time of Model 2 – without matching of
first event time of first event
Characteristics Previously Vaccinated Previously Previously
infected individuals infected infected and
(n=16,215) (n=16,215) (n=46,035) vaccinated
(n =46,035)
Age years, mean (SD) 36.1 (13.9) 36.1 (13.9) 36.1 (14.7) 36.1 (14.7)
Age group – no. (%)
16 to 39 yr 9,889 (61.0) 9,889 (61.0) 28,157 (61.2) 28,157 (61.2)
40 to 59 yr 5,536 (34.1) 5,536 (34.1) 14,973 (32.5) 14,973 (32.5)
≥60 yr 790 (4.9) 790 (4.9) 2,905 (6.3) 2,905 (6.3)
Sex – no. (%)
Female 7,428 (45.8) 7,428 (45.8) 22,661 (49.2) 22,661 (49.2)
Male 8,787 (54.2) 8,787 (54.2) 23,374 (50.8) 23,374 (50.8)
SES, mean (SD) 5.5 (1.9) 5.5 (1.9) 5.3 (1.9) 5.3 (1.9)
Comorbidities – no.
(%)
Hypertension 1,276 (7.9) 1,569 (9.7) 4,009 (8.7) 4,301 (9.3)
CVD 551 (3.4) 647 (4.0) 1,875 (4.1) 1830 (4.0)
DM 635 (3.9) 877 (5.4) 2207 (4.8) 2300 (5.0)
Immunocompromised 164 (1.0) 420 (2.6) 527 (1.1) 849 (1.8)
Obesity (BMI ≥30) 3,076 (19.0) 3,073 (19.0) 9,117 (19.8) 8,610 (18.7)
CKD 196 (1.2) 271 (1.7) 659 (1.4) 814 (1.8)
COPD 65 (0.4) 97 (0.6) 218 (0.5) 292 (0.6)
Cancer 324 (2.0) 636 (3.9) 1,044 (2.3) 1,364 (3.0)
SD – Standard Deviation; SES – Socioeconomic status on a scale from 1 (lowest) to 10; CVD –
Cardiovascular Diseases; DM – Diabetes Mellitus; CKD – Chronic Kidney Disease; COPD – Chronic
Obstructive Pulmonary Disease.

Table 1b. Characteristics of study population, model 3.
Characteristics Previously infected Previously infected and single dose
(n=14,029) vaccinated
(n=14,029)
Age years, mean (SD) 33.2 (14.0) 33.2 (14.0)
Age group – no. (%)
16 to 39 yr 9543 (68.0) 9543 (68.0)
40 to 59 yr 3919 (27.9) 3919 (27.9)
≥60 yr 567 (4.0) 567 (4.0)
Sex – no. (%)
Female 7467 (53.2) 7467 (53.2)
Male 6562 (46.8) 6562 (46.8)
SES, mean (SD) 4.7 (1.9) 4.7 (1.9)
Comorbidities
Hypertension 892 (6.4) 1004 (7.2)
CVD 437 (3.1) 386 (2.8)
DM 529 (3.8) 600 (4.3)
Immunocompromised 127 (0.9) 145 (1.0)
Obesity (BMI ≥30) 2599 (18.5) 2772 (19.8)
CKD 137 (1.0) 162 (1.2)
COPD 30 (0.2) 53 (0.4)
Cancer 241 (1.7) 267 (1.9)
SD – Standard Deviation; SES – Socioeconomic status on a scale from 1 (lowest) to 10; CVD –
Cardiovascular Diseases; DM – Diabetes Mellitus; CKD – Chronic Kidney Disease; COPD – Chronic
Obstructive Pulmonary Disease.

Table 2a. OR for SARS-CoV-2 infection, model 1, previously infected vs. vaccinated
Variable Category ß OR 95%CI P-value
Induced
Immunity
Previously infected Ref
Vaccinated 2.57 13.06 8.08 – 21.11 <0.001
SES 0.04 1.04 0.97 – 1.11 0.251
Age group, yr.
16-39 Ref
40-59 0.05 1.05 0.78 - 1.4 0.751
≥60 0.99 2.7 1.68 – 4.34 <0.001
Sex
Female Ref
Male -0.03 0.97 0.76 – 1.25 0.841
Comorbidities
Obesity (BMI≥30) 0.01 1.01 0.73 – 1.39 0.967
Diabetes mellitus -0.36 0.7 0.39 – 1.25 0.229
Hypertension 0.1 1.11 0.72 – 1.72 0.641
Cancer 0.37 1.44 0.85 – 2.44 0.171
CKD 0.53 1.7 0.83 – 3.46 0.146
COPD -0.46 0.63 0.15 – 2.66 0.529
Immunosuppression -0.1 0.91 0.42 – 1.97 0.803
Cardiovascular 0.26 1.3 0.75 – 2.25 0.343
diseases
OR – Odds Ratio; SES – Socioeconomic status on a scale from 1 (lowest) to 10; CVD –
Cardiovascular Diseases; CKD – Chronic Kidney Disease; COPD – Chronic Obstructive Pulmonary
Disease.
Table 2b. OR for Symptomatic SARS-CoV-2 infection, model 1, previously infected
vs. vaccinated
Induced
Immunity
Vaccinated 3.3 27.02 12.7 – 57.5 <0.001
SES 0.04 1.04 0.96 – 1.12 0.312
Age group, yr.
16-39 Ref
40-59 0.19 1.21 0.88 – 1.67 0.25
≥60 1.06 2.89 1.68 – 4.99 <0.001
Sex
Female Ref
Male -0.19 0.82 0.62 – 1.1 0.185
Comorbidities
Obesity (BMI≥30) 0.02 1.02 0.71 – 1.48 0.899
Hypertension 0.12 1.13 0.69 – 1.85 0.623
Cancer 0.37 1.45 0.8 – 2.62 0.217
CKD 0.1 1.1 0.42 – 2.87 0.846
COPD -0.78 0.46 0.06 – 3.41 0.445
Cardiovascular 0.03 1.03 0.52 – 2.03 0.941
diseases
Disease.
Table 3a. OR for SARS-CoV-2 infection, model 2, previously infected vs. vaccinated
Induced
Immunity
Vaccinated 1.78 5.96 4.85 – 7.33 <0.001
SES 0.07 1.07 1.03 – 1.11 <0.001
Age group, yr.
16-39 Ref
40-59 0.06 1.06 0.9 – 1.26 0.481
≥60 0.79 2.2 1.66 – 2.92 <0.001
Sex
Female Ref
Male -0.01 0.99 0.85 - 1.14 0.842
Comorbidities
Obesity (BMI≥30) 0.12 1.13 0.94 – 1.36 0.202
Hypertension -0.12 0.89 0.67 – 1.17 0.402
Cancer 0.2 1.22 0.85 – 1.76 0.283
CKD 0.3 1.35 0.85 – 2.14 0.207
COPD 0.48 1.62 0.88 – 2.97 0.121
Cardiovascular 0.08 1.09 0.77 – 1.53 0.638
diseases
Disease.
vs. vaccinated
Induced
Immunity
Vaccinated 1.96 7.13 5.51 – 9.21 <0.001
SES 0.07 1.07 1.02 – 1.12 0.003
Age group, yr.
16-39 Ref
40-59 0.09 1.1 0.9 – 1.33 0.35
≥60 0.8 2.23 1.61 – 3.09 <0.001
Sex
Female Ref
Male -0.02 0.98 0.82 – 1.16 0.785
Comorbidities
Obesity (BMI≥30) 0.16 1.18 0.95 – 1.46 0.133
Hypertension -0.01 0.99 0.72 – 1.35 0.943
Cancer 0.08 1.09 0.7 – 1.69 0.71
CKD 0.13 1.14 0.65 – 1.98 0.654
COPD 0.5 1.65 0.82 – 3.31 0.162
Immunosuppression 0 1 0.54 – 1.85 0.999
Cardiovascular 0 1 0.67 – 1.5 0.99

diseases
Disease.
Table 4a. OR for SARS-CoV-2 infection, model 3, previously infected vs. previously
infected and single-dose-vaccinated
Induced
Immunity
Previously infected -0.64 0.53 0.3 – 0.92 0.024
and vaccinated
SES 0.11 1.12 0.98 – 1.28 0.096
Age group, yr.
16-59 Ref
≥60 -0.81 0.44 0.06 – 3.22 0.422
Comorbidities
Immunosuppression 0.72 2.06 0.28 – 15.01 0.475
SES – Socioeconomic status on a scale from 1 (lowest) to 10

vs. previously infected and vaccinated
Induced
Immunity
Previously infected -0.43 0.65 0.34 – 1.25 0.194
and vaccinated
SES 0.06 1.06 0.9 – 1.24 0.508
Age group, yr.
16-59 Ref
≥60 -16.9 0 0.0 – inf 0.996
Comorbidities
Immunosuppression 1.15 3.14 0.43 – 23.01 0.26
OR – Odds Ratio; SES – Socioeconomic status on a scale from 1 (lowest) to 10.

Table S1. OR for COVID-19-related hospitalizations, model 1, previously infected
vs. vaccinated
hospitalized
Induced Immunity
Previously Ref
infected
Vaccinated 2.09 8.06 1.01 – 64.55 0.049
SES 0.05 1.05 0.72 – 1.53 0.81
Age ≥60 yrs (16-39, ref) 5.08 160.9 19.91 – <0.001
1300.44
OR – Odds Ratio; SES – Socioeconomic status on a scale from 1 (lowest) to 10
Table S2. OR for COVID-19-related hospitalizations, model 2, previously infected
vs. vaccinated
hospitalized
Induced Immunity
Previously Ref
infected
Vaccinated 1.95 7.03 2.1 – 23.59 0.002
SES -0.07 0.93 0.74 – 1.17 0.547
Age ≥60 yrs (16-39, ref) 4.3 73.5 25.09 – 215.29 <0.001
OR – Odds Ratio; SES – Socioeconomic status on a scale from 1 (lowest) to 10

Figure 1. Time of first infection in those reinfected between June and August 2021, model 2.
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medRxiv preprint doi: https://doi.org/10.1101/2021.08.24.21262415; this version posted August 25, 2021.

The copyright holder for this preprint

Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity:

The authors declare they have no conflict of interest.

Funding: There was no external funding for the project.

Corresponding author: Sivan Gazit, gazit_s@mac.org.il, 27 HaMared street, Tel Aviv,

Reports of waning vaccine-induced immunity against COVID-19 have begun to

surface. With that, the comparable long-term protection conferred by previous

infection with SARS-CoV-2 remains unclear.

We conducted a retrospective observational study comparing three groups: (1)SARS-

CoV-2-naïve individuals who received a two-dose regimen of the BioNTech/Pfizer

outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related

the Delta variant was dominant in Israel.

increased risk for symptomatic disease. SARS-CoV-2-naïve vaccinees were also at a

greater risk for COVID-19-related-hospitalizations compared to those that were

protection against infection, symptomatic disease and hospitalization caused by the

Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced

population is protected against COVID-19 at a given time in order to set healthcare

policies such as lockdowns and to assess the possibility of herd immunity.

To date, there is still no evidence-based, long-term correlate of protection1. This lack

of correlate of protection has led to different approaches in terms of vaccine resource

risk populations, potentially previously exposed.

The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer

BNT162b2 mRNA COVID-19 vaccine was demonstrated in clinical trials 2 and in

observational settings3,4. However, long term effectiveness across different variants is

long-term protection against reinfection9, there is a challenge in defining reinfection

cases will likely result in an under-estimation of the incidence of reinfection.

Different criteria based on more widely-available information have been suggested11,

apart.12 Using similar criteria, population-based studies demonstrated natural

immunity13,14 with no signs of waning immunity for at least 7 months, though

protection was lower for those aged 65 or older9.

vaccination campaign (mostly with the BioNTech/Pfizer BNT162b2 vaccine), has

official reports of decreased protection16. Concomitantly, studies have demonstrated

also explained by the correlation found between time-from-vaccine and breakthrough

infection rates, as early vaccinees were demonstrated to be significantly more at risk

protection of natural immunity compared to vaccine-induced immunity.

To this end, we compared the incidence rates of breakthrough infections to the

incidence rates of reinfection, leveraging the centralized computerized database of

Maccabi Healthcare Services (MHS), Israel's second largest Health Maintenance

Study design and population

computerized database. The study population included MHS members aged 16 or

of Health revised its guidelines and allowed previously SARS-CoV-2 infected

individuals to receive one dose of the vaccine, after a minimum 3-month-interval

from the date of infection

Anonymized Electronic Medical Records (EMRs) were retrieved from MHS’

MHS is a 2.5-million-member, state-mandated, non-for-profit, second largest health

up. The centralized dataset includes extensive demographic data, clinical

measurements, outpatient and hospital diagnoses and procedures, medications

dispensed, imaging performed and comprehensive laboratory data from a single

Data extraction and definition of the study variables

19-related hospitalizations were retrieved as well, and COVID-19-related mortality

was screened for. Additionally, information about COVID-19-related symptoms was

Exposure variable: study groups

SARS-CoV-2-naïve individuals, namely MHS members who received two doses of

We evaluated four SARS-CoV-2-related outcomes, or second events: documented

RT-PCR confirmed SARS-CoV-2 infection, COVID-19, COVID-19-related

the Delta variant became dominant in Israel.

Individual-level data of the study population included patient demographics, namely

assigned by Israel’s National Bureau of Statistics, corresponds to neighborhoods and

household income, educational qualifications, household crowding and car ownership.

about chronic diseases from MHS’ automated registries, including cardiovascular

diseases19, hypertension20, diabetes21, chronic kidney disease22, chronic obstructive

pulmonary disease, immunocompromised conditions, and cancer from the National