Abstract

METHODS

RESULTS

Overall, 673 676 MHS members 16 years and older were eligible for the study group of fully vaccinated SARS-CoV-2-naive individuals, and 62 883 were eligible for the study group of unvaccinated previously infected individuals (Supplementary Figure 1). Of those previously infected from the beginning of the pandemic and up to February 2021, who could have potentially been eligible for the study group of the unvaccinated and previously infected individuals, 693 COVID-19-related deaths were recorded. Mean age of death was 78 (SD 12), 90% of deaths were among those 60 years old and over.

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 1, model 1).

Table 1.

Characteristics of Study Population, by Model 1 and 2.

	Model 1		Model 2
Characteristics	Previously Infected (n = 16 215)	Vaccinated Individuals (n = 16 215)	Previously Infected (n = 46 035)	Vaccinated Individuals (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	9889 (61.0)	9889 (61.0)	28 157 (61.2)	28 157 (61.2)
40 to 59 yr	5536 (34.1)	5536 (34.1)	14 973 (32.5)	14 973 (32.5)
≥60 yr	790 (4.9)	790 (4.9)	2905 (6.3)	2905 (6.3)
Sex, no. (%)
Female	7428 (45.8)	7428 (45.8)	22 661 (49.2)	22 661 (49.2)
Male	8,787 (54.2)	8787 (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	1276 (7.9)	1569 (9.7)	4009 (8.7)	4301 (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)	3076 (19.0)	3073 (19.0)	9117 (19.8)	8610 (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)	1044 (2.3)	1364 (3.0)

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Abbreviations: BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; DM, diabetes mellitus; SD, standard deviation; SES, socioeconomic status on a scale from 1 (lowest) to 10.

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) (Supplementary Figure 2). 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 < .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 2). To further characterize the association with older age, we added an interaction analysis which yielded a non-statistically significant (P = .79) interaction term of age ≥60 years, vaccination and risk for incidence infection.

Table 2.

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	<.001
SES		0.04	1.04	.97–1.11	.251
Age group, yr
	16−39	Ref
	40−59	0.05	1.05	.78–1.4	.751
	≥60	0.99	2.7	1.68–4.34	<.001
Sex
	Female	Ref
	Male	−0.03	0.97	.76–1.25	.841
Comorbidities
	Obesity (BMI ≥30)	0.01	1.01	.73–1.39	.967
	Diabetes mellitus	−0.36	0.7	.39–1.25	.229
	Hypertension	0.1	1.11	.72–1.72	.641
	Cancer	0.37	1.44	.85–2.44	.171
	CKD	0.53	1.7	.83–3.46	.146
	COPD	−0.46	0.63	.15–2.66	.529
	Immunosuppression	−0.1	0.91	.42–1.97	.803
	Cardiovascular diseases	0.26	1.3	.75–2.25	.343

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Abbreviations: BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; OR, odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SES, socioeconomic status on a scale from 1 (lowest) to 10.

The E-value for breakthrough infection was 25.61 (and 15.64 for the lower bound of the CI). Thus, an unmeasured confounder not included in the regression model associated with both a 2-dose vaccination and with a breakthrough infection outcome by an OR of 25.61 each could explain away the lower confidence limit, though a weaker confounder would not.

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 reverse transcription polymerase chain reaction (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 < .001) (Supplementary Table 1). None of the covariates were significant, except for age ≥60 years. The sensitivity analyses that adjusted for individuals’ test frequency as a proxy for healthcare seeking behavior did alter results (Supplementary Data).

Eight cases of COVID-19-related hospitalizations were recorded, all of which were in the vaccinated group, and 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) (Table 1). Figure 1 demonstrates the timely distribution of the first infection in reinfected individuals.

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Figure 1.

Time of first infection in those reinfected between June and August 2021, model 2.

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 < .001) (Table 3). 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. The E-value for breakthrough infection was 11.4 (and 9.17 for the lower bound of the CI).

Table 3.

OR for SARS-CoV-2 Infection, Model 2, Previously Infected vs Vaccinated

Variable	Category	ß	OR	95% CI	P-value
Induced immunity
	Previously infected	Ref
	Vaccinated	1.78	5.96	4.85–7.33	<.001
SES		0.07	1.07	1.03–1.11	<.001
Age group, yr
	16–39	Ref
	40–59	0.06	1.06	.9–1.26	.481
	≥60	0.79	2.2	1.66–2.92	<.001
Sex
	Female	Ref
	Male	−0.01	0.99	.85–1.14	.842
Comorbidities
	Obesity (BMI ≥30)	0.12	1.13	.94–1.36	.202
	Diabetes mellitus	−0.15	0.86	.61–1.22	.4
	Hypertension	−0.12	0.89	.67–1.17	.402
	Cancer	0.2	1.22	.85–1.76	.283
	CKD	0.3	1.35	.85–2.14	.207
	COPD	0.48	1.62	.88–2.97	.121
	Immunosuppression	−0.03	0.98	.57–1.66	.925
	Cardiovascular diseases	0.08	1.09	.77–1.53	.638

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Abbreviations: BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; OR, odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SES, socioeconomic status on a scale from 1 (lowest) to 10.

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 (Supplementary Table 2). COVID-19 related hospitalizations occurred in 1 and 19 of the reinfection and breakthrough infection groups, respectively. No COVID-19-related deaths were recorded. Similarly to model 1, a sensitivity analysis adjusting for the frequency of testing did not materially alter the OR for infection or symptomatic infection (Supplementary Data).

A second sensitivity analysis accounted for the timing of vaccination. We matched 46 818 persons in each group (previously infected vs later vaccinees, namely those vaccinated between March and April 2021) (Supplementary Table 7). When comparing the later vaccinees to those previously infected at any time (from 2020), 570 cases of SARS-CoV-2 infection were recorded, 463 of which were in the March–April vaccinated group (breakthrough infections) and 107 in the previously infected group (reinfections). After adjusting for comorbidities, a 4.63-fold increased risk (95% CI: 3.53 to 5.38) for breakthrough infection as opposed to reinfection could be observed (Supplementary Table 8). As for symptomatic cases, there was a 6.67-fold (95% CI: 4.9 to 9.06) increased risk for symptomatic breakthrough infection than symptomatic reinfection (Supplementary Table 9). There were 7 cases of COVID-19 related hospitalizations, 4 of which among the April–March vaccinees and 3 among the previously infected. Lastly, the sensitivity analysis that included an alternative model (Cox proportional hazards regression) yielded similar results (Supplementary Data).

DISCUSSION

This is the largest real-world observational study comparing naturally acquired 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 first 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 naturally acquired 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-naive vaccinees had more COVID-19-related-hospitalization compared to those who were previously infected, although the numbers are too small to determine statistical significance. Importantly, in neither group no COVID-19-related deaths were recorded.

The advantageous protection afforded by naturally acquired 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 vaccine [19, 20]. However, as a correlate of protection is yet to be proven [1, 21], including the role of B-Cell [22] and T-cell immunity [23, 24], this remains a hypothesis. Our study matches the CDC report [10], examining cohorts in California and New York, demonstrating that infection-induced protection was more substantial than vaccine induced immunity during the Delta period. The report demonstrates an opposite trend during the previous Alpha dominant period; however, a significant limitation, addressed as such by the researchers of this report as well, pertains to the lack of addressing the varying times-since-vaccination, which could bias the result, especially in the early stages of the follow-up.

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, including the Omicron variant. 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, an assessment that might require more data before carrying out. Additionally, as this is an observational real-world study, where PCR screening was not performed by a pre-set protocol, we might be underestimating asymptomatic infections, as these individuals often do not get tested. A related concern is that the frequency of PCR testing differed between groups, meaning that 1 group manifested different health seeking behavior during the pandemic and therefore is potentially more diagnosed rather than more infected. To address that potential detection bias, we conducted a sensitivity analysis where the number of PCR tests undertaken throughout the pandemic was adjusted for, as a proxy for COVID-19-related health seeking behavior. The findings demonstrated that this adjustment did not change the results. Furthermore, the analysis merits addressing the potential survivorship bias, which might have accounted for the stronger protection of the unvaccinated previously infected group. As reported in the results, COVID-19 related mortality in this group (prior to the outcome period) was evaluated at approximately 1% with mean age of 78 years. Therefore, it does not seem to overall account for the significant protection conferred by natural infection across the different age groups. Moreover, as individuals with chronic illness were primarily vaccinated between December and February, confounding by indication needs to be considered; though the groups somewhat differ in their comorbidity profile, adjusting for obesity, cardiovascular disease, diabetes, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, cancer, and immunosuppression had only a small impact on the estimated effect as compared to the unadjusted OR. Therefore, residual confounding by unmeasured factors is unlikely. Nonetheless, to assess whether the association between previous infection or vaccination and a following infection (breakthrough- or re-infection) could be attributed to unmeasured confounding, for example, by differential groups behavior (such as social distancing and mask wearing), we calculated the E-value for an unmeasured confounding. The E-value for both models suggested that only a highly strong association between both the group (vaccinated vs previously infected individuals) and healthcare seeking behavior, and healthcare seeking behavior and the outcome of a subsequent infection (breakthrough- or reinfection) would account for all the observed association between vaccinating convalescent patients and their reduced risk for reinfection.

To further address this issue, we conducted a different sensitivity analysis, where we implemented the same design of model 2, comparing those previously infected at any time to later vaccinees, namely those who completed the second dose between March and April 2021. This time, the latter group had slightly more comorbidities than those previously infected, though again these were not found to affect significantly. The results suggest waning of vaccine-induced immunity against the Delta variant and still point to an increased risk of those vaccinated. Those later vaccinees are at a 4.63-fold increased risk for breakthrough infection and at a 6.67-fold increased risk for symptomatic disease compared to those previously infected. Lastly, as per Israeli regulations the second dose was administered within 21–28 days of the first dose, we could not assess whether an extended interval between the doses affects effectiveness. This analysis demonstrated that naturally acquired immunity affords longer lasting and stronger protection against infection and symptomatic disease due to the Delta variant of SARS-CoV-2, compared to the BNT162b2 2-dose vaccine-induced immunity.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

NOTES

Financial support. There was no external funding for the project.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References