Risk Of SARS-CoV-2 Reinfection And COVID-19 Hospitalisation in Individuals With Natural And Hybrid Immunity: A Retrospective, Total Population Cohort Study in Sweden Part 2

Study definitions

No immunity was defined as being unvaccinated and not having a documented previous SARS-CoV-2 infection at baseline. Natural immunity was defined as having a documented previous infection but being unvaccinated at baseline. 

Natural immunity refers to the human body's natural ability to resist foreign pathogens. It is one of the important factors in maintaining human health. Memory is an important manifestation of human wisdom, which affects our study, work, and life. Is there a connection between the two?

The answer is yes. Scientific research has found that the immune system and the nervous system influence each other. The immune response has subtle connections with sensory neurons and the central nervous system. They regulate and control each other, forming a two-way regulatory relationship. Therefore, we can find that immunity and memory are related to each other.

First of all, the role of immunity in memory is obvious. Once our immunity is attacked by pathogens, it will initiate an immune response and consume a lot of energy, leading to physical fatigue and weakness. At this time, people will experience memory decline. Therefore, adequate rest, a healthy lifestyle, and a strong immune system will help improve memory.

Secondly, good memory also plays an important role in immunity. Our brain uses memory to activate the antibody response, the occurrence and proliferation of T cells and B cells in the immune system, and enhance the body's immunity. Therefore, a person with a good memory is more likely to have a protective and preventive effect on disease than a person with negative emotions.

To sum up, the relationship between natural immunity and memory is inseparable. To improve immunity, we should pay attention to maintaining a healthy lifestyle, actively participate in sports and exercise, and eat more foods rich in protein, vitamins, and trace elements. At the same time, constantly exercising the brain and improving memory can also help enhance immunity. Only with a strong body and an agile brain can we show a better state of life in life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

Click know supplements to improve memory

One-dose hybrid immunity was defined as having a documented previous infection and having received a single dose of either ChAdOx1 nCoV-19 (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) either before or after infection at baseline. 

Two-dose hybrid immunity was defined as having a documented previous infection and having received two doses of any of the vaccines at baseline, with at least the second dose given after the infection.

Outcomes

This study had two outcomes. The first outcome was SARS-CoV-2 infection as documented in the SmiNet register from March 20, 2020, until Oct 4, 2021. Given that all confirmed infections are documented in this register, this outcome was defined as a SARS-CoV-2 infection of any severity for the present study. 

The second outcome was inpatient hospitalization with COVID-19 as the main diagnosis and reason for admission, traced using the National Inpatient Register and the International Classification of Disease (ICD) version 10 code U071. 

This register is managed by the National Board of Health and Welfare. Hospitalizations in the cohorts could be tracked from March 30, 2020, until Sept 5, 2021. Only hospitalizations and infections that occurred more than 14 days after baseline were evaluated. 

Planned follow-up for assessment of outcomes was 20 months for cohort 1 and 9 months for cohorts 2 and 3, and follow-up time in days was counted until the date of either a confirmed SARS-CoV-2 infection or COVID-19 hospitalization, a vaccination after baseline (for unvaccinated individuals and individuals with one-dose hybrid immunity), death, or end of possible follow-up time (Oct 4, 2021, for the infection outcome and Sept 5, 2021, for the hospitalization outcome), whichever occurred first.

Statistical analysis

Hazards over time for the outcome of SARS-CoV-2 infection based on immunity status were illustrated using proportional hazards models with 95% CIs and restricted cubic splines. The knots were placed in the default position. To compare the risk of both outcomes (SARS-CoV-2 infection and COVID-19 hospitalization) based on immunity status, Cox regression was used to calculate hazard ratios (HR). 

To adjust for the matched samples, 95% CIs were estimated using robust standard errors by the variance–covariance matrix (VCE) command and robust option in Stata. To formally test whether the associations were time-dependent, Schoenfeld's residuals were evaluated using the estate test command in Stata. Because the test indicated that the proportional hazard assumption was violated (p<0·05) for some of the main exposures, the associations were also evaluated in time intervals in the cohorts. 

In all cohorts, the first model was adjusted for age and baseline date, to account for variations in infection pressure during follow-up (reported as HR). The second model included the additional covariates sex, homemaker service (yes or no), education (six categories), marital status (five categories), whether the individual was born in Sweden or not, and nine diagnoses at baseline (yes or no; reported as adjusted [a]HR). 

To investigate whether there was an effect measure modification of the associations between the exposure and outcome by any of the covariates, interaction analyses were done using product terms created by multiplying the variable coding for immunity status at baseline by each respective covariate, which was added to the fully adjusted Cox model. Given that the interaction terms were significant (p<0·001) for many covariates, associations were investigated in subgroups according to these covariates, including the type of vaccine for two-dose hybrid immunity compared with natural immunity. 

Other subgroup analyses were by age, sex, comorbidity status (compared with the total population), and homemaker service (compared with the total population). The covariates were selected a priori based on a previous study in a similar population.25 For the diagnoses of interest, the National Inpatient Register was used to obtain information about inpatient care since the beginning of 1998, and the National Outpatient Register was used to obtain information on outpatient specialist care since the beginning of 2001. 

Information about prescribed drugs of interest at baseline and death during follow-up was obtained using the Prescribed Drug Register from the beginning of 2014 onwards and the Cause of Death Register, respectively, which is also managed by the National Board of Health and Welfare. Information about homemaker services (ie, help from the community with housekeeping tasks that older people can no longer perform) was also obtained from the National Board of Health and Welfare. Birth year and month, country of birth, marital status, level of highest education, and sex for all individuals in the cohort were obtained from Statistics Sweden. 

Definitions of comorbidities are provided in Appendix p 2. All analyses were done using SPSS version 27.0 for Mac and Stata version 16·1 for Mac. A two-sided p-value of less than 0·05 or an HR with a 95% CI not crossing 1 was considered significant. In the two-dose hybrid immunity versus natural immunity cohort, the number needed to vaccinate to prevent one reinfection in individuals with natural immunity was estimated as the difference in event rate between the two groups, inverted.

Results

According to the SmiNet register, 94·4% of infections were confirmed using PCR, 4·8% through sequencing, and the remaining through a combination of methods. In cohort 1 (natural immunity vs no immunity), the mean baseline date was Jan 1, 2021, and the median age was 39·2 years (IQR 25·5–53·0; Table 1). 

Individuals in cohort 2 (one-dose hybrid immunity vs natural immunity) had a median age of 39·9 years (28·3–52·4) at baseline and the mean baseline date was June 7, 2021, more than 6 months later than the baseline date in cohort 1, with a lower resulting infection pressure during follow-up, since individuals in cohort 2 and 3 missed the first wave, and shorter follow-up time. Individuals in cohort 3 (two-dose hybrid immunity vs natural immunity) had a median age of 37·6 years (27·8–50·3) with a baseline date of July 9, 2021.
Individuals with natural immunity in the second and third cohorts were more often born outside of Sweden than those with natural immunity in the first cohort. Participant characteristics at different time intervals during follow-up in the cohorts are in the appendix (pp 3–4). The number of confirmed SARS-CoV-2 infections in Sweden during follow-up, and SARS-CoV-2 variants sequenced in Sweden during the study period, are shown in the appendix (pp 5, 8). 

During the study period, there were three large waves of COVID-19. The first two waves (in March–June 2020, and October 2020, to January 2021) occurred before the sequencing data were available, and before the alpha variant became dominant in Sweden. Based on the sequencing data, the alpha variant dominated during the third wave (in February–May 2021), and the delta variant dominated from July 2021, onwards (thus including the fourth wave that started in August 2021). 

During a mean follow-up of 164 days (SD 100), 34090 individuals with natural immunity were registered as having had a SARS-CoV-2 reinfection compared with 99168 infections in non-immune individuals. Compared with no immunity, natural immunity was associated with a gradually reduced risk of reinfection during the first 3 months of follow-up (figure 2A). After 3 months, the associated risk reduction was 95% (aHR 0·05 [95% CI 0·05–0·05]; p<0·001), with no signs of attenuation for up to 20 months of follow-up (figure 2A; table 2). 

The associations appeared to attenuate with increasing age (table 2), in people born outside Sweden (data not shown), with increasing education level (data not shown), and in people receiving a homemaker service (table 2; p<0·001 for all). For the outcome of COVID-19 hospitalization (table 3), 3195 people with natural immunity were hospitalized and 1976 people with no natural immunity were hospitalized; natural immunity was associated with increased risk during the first 3 months of follow-up, but from 3 months onwards there was an associated 87% lower risk of COVID-19 hospitalization in people with natural immunity than in people with no immunity (aHR 0·13, 95% CI 0·11–0·16, p<0·001) for up to 19 months of follow-up. 

The associations were weaker with increasing age and in individuals receiving a homemaker service (both p<0·001). During a mean follow-up of 52 days (SD 38), 639 individuals with one-dose hybrid immunity were registered with a SARS-CoV-2 reinfection, compared with 1662 individuals with natural immunity (appendix p 6). The associations attenuated with increasing follow-up time (figure 2B, p<0·001). 

Thus, during the first 2 months of follow-up, compared with natural immunity, one-dose hybrid immunity was associated with a 58% lower risk of reinfection (aHR 0·42 [95% CI 0·38–0·47]; p<0·001), which was reduced to 45% (0·55 [0·39–0·76]; p<0·001) from 2 months onwards. Overall, the associations were weaker in older individuals, in individuals with homemaker service (p<0·001), and in individuals with comorbidities (p<0·001; appendix p 6).
Concerning COVID-19 hospitalizations, eight individuals were hospitalized among individuals with one dose hybrid immunity (incidence rate [IR] 0·04) compared with 113 individuals with natural immunity (IR 0·56; HR 0·06 [95% CI 0·03–0·12]; p<0·001). During a mean follow-up of 66 days (SD 53), 438 individuals with two-dose hybrid immunity were registered as having had a SARS-CoV-2 reinfection, compared with 808 individuals with natural immunity (appendix p 7). Correspondingly, the number of individuals with natural immunity needed to be double vaccinated to prevent one reinfection during follow-up was 767. Overall, two-dose hybrid immunity was associated with a 66% lower risk of reinfection than natural immunity (aHR 0·34 [95% CI 0·31–0·39]; p<0·001). 

During the first 2 months of follow-up, two-dose hybrid immunity was associated with a 69% (0·31 [0·26–0·36]; p<0·001) lower risk of reinfection than natural immunity. From 2 months onwards, the associated risk reduction was 56% (0·44 [0·35–0·56]; p<0·001), with no significant attenuation up to 9 months (p=0·07; figure 2C). Overall, the associations were slightly weaker in older individuals, in individuals with homemaker service (p<0·001), and in individuals with comorbidities (p<0·001; (appendix p 7). 

Concerning vaccine types, a significant association was observed for mRNA vaccines (aHR 0·32 [95% CI 0·28–0·37]; p<0·001) but not ChAdOx1 nCoV-19 (0·75 [0·41–1·37]; p=0·35; appendix p 7). Concerning COVID-19 hospitalizations, six individuals with two-dose hybrid immunity were hospitalized (IR 0·04) compared with 40 individuals with natural immunity (IR 0·44; HR 0·10 [95% CI 0·04–0·22]; p<0·001).

Discussion

In this nationwide study, immunity acquired from a previous infection was associated with a low risk of SARS-CoV-2 reinfection and COVID-19 hospitalization for up to 20 months. In head-to-head comparisons, immunity acquired from a previous infection plus either one or two doses of a COVID-19 vaccine was associated with a greater reduced risk of SARS-CoV-2 reinfection and COVID-19 hospitalization for up to 9 months than previous infection only, although with small differences in absolute numbers during follow-up. 

Many authorities recommend that all individuals should receive both primary series vaccination and booster vaccination irrespective of whether they have previously been infected. The strongest argument behind this recommendation might be the scarcity of evidence on long-term protection from natural immunity. A meta-analysis of 15 observational studies showed that natural immunity was associated with an 87% lower risk of reinfection than non-immunity for up to 1 year.13 Our study extends the body of evidence with up to 20 months of follow-up and more than 130000 documented SARS-CoV-2 infections, and our results showed that individuals with natural immunity had an associated 95% protection against SARS-CoV-2 reinfection during follow-up (from 3 months after initial infection until 20 months), with no signs of waning. 

These results indicate that natural immunity might be better maintained than immunity induced by vaccination only, as suggested also by preliminary data from an Israeli study.19 In further support of our findings, we recently reported waning vaccine effectiveness against SARS-CoV-2 infection within a few months in a similar study based on the total population of Sweden.26 

Another important finding of the present study is the association between natural immunity and later hospitalization for reinfection, which has not previously been reported in the literature. As expected, there was an increased risk of hospitalization during the first 3 months after the first infection, but for those who survived, natural immunity was associated with 87% protection against COVID-19 hospitalization during the rest of the follow-up. The associated level of protection remained high (78%) even from 9 up to 19 months of follow-up, altogether indicating long-lasting protection, including against severe disease, from natural immunity. 

Together, these findings might suggest that any passports or documents used to identify whether a person is immune or not, and used for societal restrictions, should acknowledge either a previous infection or vaccination as proof of immunity, as opposed to vaccination only. This policy could have social and equity implications, especially for individuals in countries with low vaccine coverage, considering also that the dominant omicron variant is less sensitive to current vaccines than previous variants.27 The associated protection from natural immunity was lower in older individuals and in individuals receiving a homemaker service, as previously reported in a nationwide study from Denmark.28 

Because these individuals have a higher risk of critical illness and death from COVID-19,24,29 boosting their level of protection is important. Thus, as further shown through head-to-head comparisons, individuals who had recovered from a previous infection had an additional associated protection against SARS-CoV-2 reinfection if they had also been vaccinated, although the associations appeared slightly weaker in older individuals. The associated benefit seemed slightly stronger and more stable for those given two doses rather than one dose of vaccine, and it was more clearly detectable among those vaccinated with mRNA vaccines than ChAdOx1 nCoV-19 (in whom the association was weaker and not significant, although the number of participants contributing to this analysis was small). This finding is supported by a systematic review and meta-regression of vaccine effectiveness studies, which suggested faster waning of immunity with ChAdOx1 nCoV-19 than with BNT162b2.30 In the present study, there was also evidence of waning protection, especially for those with one-dose hybrid immunity. 

Waning protection from hybrid immunity was observed also in a recent Israeli preprint study of 5·7 million individuals.19 Additionally, the absolute risk reduction associated with hybrid immunity in the present study was small, indicating that to prevent one SARS-CoV-2 reinfection among those with natural immunity, 767 individuals would need to be vaccinated with two doses. Similar results were reported in an Israeli preprint study including 14 029 matched pairs,31 in which one additional dose of vaccine in those with natural immunity was associated with seven fewer cases of symptomatic reinfection, suggesting that about 2000 individuals needed to be vaccinated to prevent one reinfection. 

If these associations are causal, the overall clinical relevance of these effects appears uncertain. In the present study, both one-dose and two-dose hybrid immunity were associated with protection against COVID-19 hospitalization that was above the level of protection afforded by natural immunity. Because the primary aim of COVID-19 vaccination is to prevent severe disease, this finding is important. However, hospitalizations were rare, and because these analyses were based on a small number of cases, further studies should seek to assess the duration of protection of hybrid immunity against severe COVID-19. 

This study has limitations that should be considered. First, the observational nature of the study limits the possibility of drawing causal inferences, and there might be unknown confounding or biases not accounted for. For example, there is a risk of selection bias in individuals without a previous infection because they might be less inclined to take a PCR test than individuals with a documented previous infection, although this bias would not affect the estimates for the outcome of COVID-19 hospitalization. Furthermore, as individuals with a previous infection were censored upon vaccination, the remaining cohort might have become less representative as time passed, introducing another selection bias. 

Although the associations were stable after adjustment for a rather rich set of covariates, the possibility of unmeasured confounding or bias remains. Moreover, in the analysis of hybrid immunity versus natural immunity, vaccinated individuals with symptoms of infection may be more prone to self-testing than individuals who remain unvaccinated after a documented infection. If so, this behavior would attenuate the associations for the outcome of infection; however, it would not affect the associations with hospitalization. Second, the mean baseline date was not the same in all cohorts, which could mean that variations in infection pressure and dominating SARS-CoV-2 variants during follow-up influenced the results, although we adjusted all models for baseline data. Third, we could not evaluate how different variants of SARS-CoV-2 influenced the associations, as we did not have access to such data on an individual level. 

Fourth, although individuals with a documented previous infection were excluded from the non-immune cohort, individuals with a previous asymptomatic infection might still have been included. Similarly, there is a risk of misclassification bias (ie, false-positive and false-negative tests, which could potentially result in underestimated associated benefits of natural immunity vs no immunity). However, the PCR test has been estimated to have a 97·1% sensitivity and 99·9% specificity.32 Fifth, it cannot be determined to what extent the results apply to the omicron variant. 

However, a study found that previous infection was associated with about 60% protection against symptomatic reinfection and about 90% protection against severe reinfection (hospitalization or death) with the omicron variant.33 Strengths of the present study include the use of registers with 100% nationwide coverage and a follow-up time of up to 20 months for the exposure of natural immunity and up to 9 months for hybrid immunity. Another strength is the head-to-head comparisons of hybrid immunity versus natural immunity, in which individuals in each pair were matched on birth year, had similar baseline characteristics, and started follow-up on the same date, and in which several covariates were adjusted for. Together, these methods reduce the risk of confounding when the aim is to perform direct comparisons. Finally, the large, population-based sample size increases the generalisability of the results to other countries with similar population structures.

Contributors

All authors conceived and designed the study. PN acquired the data and did the statistical analyses. PN and MB accessed and verified the underlying data and drafted the manuscript. PN and AN supervised the work. All authors interpreted the data, critically revised the manuscript for intellectual content, gave final approval of the version to be published, had full access to all the data, and had final responsibility for the decision to submit for publication.

Data Sharing

The data files used for the present study are publicly unavailable according to regulations under Swedish law. However, access to all the data used for the present study can be requested from the National Board of Health and Welfare, Statistics Sweden, and the Public Health Agency of Sweden.

References 

1 Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med 2020; 383: 2603–15. 

2 Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384: 403–16. 

3 Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. Lancet 2021; 397: 99–111. 

4 Chemaitelly H, Yassine HM, Benslimane FM, et al. mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar. Nat Med 2021; 27: 1614–21. 

5 Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of COVID-19 vaccines against the B.1.617.2 (delta) variant. N Engl J Med 2021; 385: 585–94. 

6 Nordström P, Ballin M, Nordström A. Effectiveness of heterologous ChAdOx1 nCoV-19 and mRNA prime–boost vaccination against symptomatic COVID-19 infection in Sweden: a nationwide cohort study. Lancet Reg Health Eur 2021; 11: 100249. 

7 Chung H, He S, Nasreen S, et al. Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada: test negative design study. BMJ 2021; 374: n1943. 

8 Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine through 6 months. N Engl J Med 2021; 385: 1761–73. 

9 El Sahly HM, Baden LR, Essink B, et al. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N Engl J Med 2021; 385: 1774–85. 

10 Falsey AR, Sobieszczyk ME, Hirsch I, et al. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine. N Engl J Med 2021; 385: 2348–60.

For more information:1950477648nn@gmail.com