Damian Sendler: It’s estimated that by early 2022, more than a third of the world’s population would have been exposed to a strain of SARS-CoV-2. To prevent SARS-CoV-2 reinfection and severe illness in the future, it is imperative that natural immunity, which has been shown to be effective and long lasting in infected individuals, be as effective as possible. An overview of epidemiological research on this topic is provided in this narrative review. SARS-CoV-2 infection is linked with a greatly decreased risk of reinfection, with effectiveness lasting at least one year and only mild decreasing immunity, according to national surveys conducted between 2020 and 2021. Except for the Omicron variation, where data are still coming before definitive conclusions can be reached, natural immunity exhibited relatively identical effect sizes in terms of protection against reinfection across various SARS-CoV-2 variants. Reinfections of SARS-CoV-2 also lowered the risk of hospitalizations and mortality. SARS-CoV-2 infections may be prevented by natural immunity as well as by two doses of an mRNA vaccine, however the findings are not completely consistent, according to observational studies. The best protection against SARS-CoV-2 infections seems to come from a combination of prior infection with SARS-CoV-2 and a corresponding vaccine, known as hybrid immunity. However, there are still many questions about this topic. SARS-CoV-2 public health strategy should take into account natural immunity.
Damian Jacob Sendler: A worldwide pandemic of coronavirus illness 2019 was triggered by the breakout of SARS-CoV-2 in December 2019 in China (COVID-19) (Wu and McGoogan, 2020; Singh et al., 2021). When making decisions on how to combat SARS-CoV-2 infections, it is important to consider the pros and cons of various options and to gather scientific evidence to support those choices (Ioannidis, 2020a; Kampf and Kulldorff, 2021; Pilz, 2021). When tested in clinical settings, the SARS-CoV-2 vaccine has been shown to be extremely effective in short-term randomized controlled trials (RCTs) (Khandker et al., 2021; McIntyre et al., 2022; Polack et al., 2020; Sharif et al., 2021). As early as a few months following vaccination, reports of diminishing immunity represent a challenge to public health policies (Chemaitelly et al., 2021b; Goldberg et al., 2021b; Levin et al., 2021; Rosenberg et al., 2022). Booster immunizations may help reestablish a high level of protection against SARS-CoV-2 infections and consequent death, according to new research (Arbel et al., 2021; Bar-On et al., 2021a, 2021b; Chemaitelly et al., 2021b; Goldberg et al., 2021b; Levin et al., 2021; Rosenberg et al., 2022). There is some uncertainty about the frequency of boosters (if any) required in various age groups, and the absolute advantages may be significantly larger in immunocompromised and elderly patients, given the steep age-gradient of COVID-19 infection mortality rates (Axfors and Ioannidis, 2022). With the emergence of novel strains like Omicron, the capacity to establish adequate protection against infection and transmission is under question (Buchan et al., 2022). SARS-CoV-2 infection-related natural immunity may be an important but underappreciated feature in the development of sophisticated vaccination methods and general interventions against COVID-19 (Ioannidis, 2020b; McIntyre et al., 2022).
Damian Sendler
Dr. Sendler: SARS-CoV-2 may have already infected more than a third of the world’s population by the beginning of the COVID-19 pandemic, with many of the cases being unreported, and this knowledge might be crucial to preventing a resurgence of the disease and its associated morbidity and mortality (Bergeri et al., 2021; Hotez et al., 2021; McIntyre et al., 2022). This estimate is based on seroprevalence data that shows that by spring 2021, about a quarter of the world’s population had been infected with the Delta variant waves since mid-2021 and then the massive surges of the Omicron variant starting in December of that year (Arora et al., 2021; Bergeri et al., 2021; Chen et al., 2021; Ioannidis, 2021c; Jones et al., 2021). High-income nations are presently able to identify and report around every second SARS-CoV-2 case, while in low-income countries, the ratio between genuine and reported cases seems to have been about 62 to 1 in a systematic study that included data through October 2021. (Bergeri et al., 2021). As more testing is done in low-income nations, this ratio may have reduced over time, but it is still likely to be widespread in these countries. Serum prevalence was approximately 70% in India in August 2021, whereas recorded cases were just 2%, based on a countrywide serosurvey (Jahan et al., 2021). Asymptomatic situations are quite prevalent, as a result of this. Even among individuals with confirmed COVID-19, 40.5% were asymptomatic, according to a recent meta-analysis (Ma et al., 2021). There may be an even greater number asymptomatic instances with the introduction of the new Omicron strain. The percentage of those infected with Omicron is expected to rise significantly as the disease spreads even more rapidly (Christie, 2021; Del Rio et al., 2022; Kupferschmidt and Vogel, 2021). It may soon be an exception to find someone who has not been exposed to SARS-CoV-2 at least once when the epidemic enters its endemic phase.
With this narrative review, I’d want to briefly summarize what we now know about the effectiveness and longevity of natural immunity based on large epidemiological studies of broad populations, ideally nationwide surveys.. Additionally, this analysis includes comparisons of natural immunity vs vaccine-induced immunity and so-called hybrid immunity, which is produced through SARS-CoV-2 infection and vaccination. Our research is based on a PubMed search for the phrases “SARS-CoV-2” or “COVID-19” with the word “reinfection” until January 1, 2022. (yielding 891 items). When searching medRxiv, the same search strategy was used, but only items of exceptional interest were included (with care). Our research greatly expands and updates earlier studies on this subject (Kojima et al., 2021; Petras, 2021; Shenai et al., 2021). Despite the fact that this manuscript focuses on epidemiological data regarding natural immunity, we recommend that the reader refer to excellent reviews on the detailed immunological responses to SARS-CoV-2 infections and vaccinations, as we only briefly touch upon these issues in some sections of our report (Castro Dopico et al., 2022; Cromer et al., 2021; Gussarow et al., 2021; Milne et al., 2021).
Damian Jacob Markiewicz Sendler: Study on 133,266 previously SARS-CoV-2 infected patients from Qatar found that the probability of reinfection was assessed at 0.02% (95 percent confidence interval: 0.01%–0.02%) and that the reinfection incidence rate per 10,000 person weeks was 0.36% (95 percent confidence interval: 0.28%–0.57%). (Abu-Raddad et al., 2021e). Natural SARS-CoV-2 infection had a 95% success rate against reinfection, according to this research, which did not involve a formal group comparison with previously uninfected patients. The first cohort studies in particular populations are expected to conclude by the end of 2020 and the beginning of 2021 that SARS-CoV-2 infections are dramatically decreased in individuals who have previously been infected with the virus (Breathnach et al., 2021b; Hall et al., 2021; Hanrath et al., 2021; Kojima et al., 2021; Lumley et al., 2021a). One of the earliest studies on this topic was reported by Lumley et al. in a cohort of 12,541 health care professionals who were well-characterized by PCR and antibody testing (Lumley et al., 2021a). They found that those who had previously been infected with SARS-CoV-2 had an 89 percent (95 percent CI: 44 percent –97 percent) level of protection against SARS-CoV-2 infection (Lumley et al., 2021a). Austrian and Danish national surveys were the first to look at this problem, along with a major US cohort research based on seroprevalence data (Hansen et al., 2021; Harvey et al., 2021; Pilz et al., 2021). SARS-CoV-2 infections were reduced by 90% (95 percent CI: 81 percent – 95 percent) in individuals with positive vs negative antibody tests for SARS-CoV-2 in the later research, which comprised 3,257,478 participants (Harvey et al., 2021). A population-based study in Qatar of 192,984 people with accessible SARS-CoV-2 antibody test results indicated a natural immunity effectiveness of 95.2% (95 percent CI: 94.1 percent –96.0 percent) based on antibody status, in accordance with this (Abu-Raddad et al., 2021d).
Damian Jacob Sendler
Research in Table 1 are all peer-reviewed studies, except for one from the United States that included antigen testing in addition to PCR tests, and a study from the United Kingdom that categorised infection status at baseline based on PCR or antibody tests (Breathnach et al., 2021b; Spicer et al., 2021). While the research in Table 1 include a variety of infection waves, there is no data on Omicron’s version. It has been shown that compared to the Beta or Delta versions, the Omicron form has the greatest capacity for evading immunity from past infection (Lusvarghi et al., 2021). As a result, further data from SARS-CoV-2 Omicron variant infections will be needed to update our understanding of natural immunity. Omicron’s ability to protect against reinfections may be reduced to 56.0 percent (95 percent CI: 50.6 percent–60.9 percent), but its ability to protect against hospitalization or death due to reinfections appears to be similar to other variants with 87.8 percent (95 percent CI: 47.5 percent–97.1 percent) (Altarawneh et al., 2022). However, there are conflicting preliminary findings on Omicron’s innate immunity, necessitating careful interpretation (Eggink et al., 2021; Pulliam et al., 2021). Table 1 focuses on studies in general populations, but there are numerous studies on this topic in specific populations (e.g. health care workers) or with other study designs (e.g. solely based on antibodies with thus unclear infection date or missing control groups) that all support the notion that natural immunity significantly protects against SARS-CoV-2 infections (Abrokwa et al., 2021; Fabianova et al., 2021; Hall et al., 2021; Hanrath et al., 2021; Harvey et al., 2021; Iversen et al., 2021; Jeffery-Smith et al., 2021; Kojima et al., 2021; Leidi et al., 2021; Letizia et al., 2021; O Murchu et al., 2021; Rennert and McMahan, 2021).
The effectiveness of natural immunity has been evaluated using a variety of methods. In the case of a test-negative research, it may be appropriate to include a remark (Ayoub et al., 2022). When a person comes in for testing because of symptoms, this strategy selects cases and matched, negative controls. Prior infection’s ability to prevent re-infections is estimated by dividing the probabilities of previous infection in persons who tested negative by those who tested positive. See Lewnard et al. for cautions on the test-negative design’s robustness (2021).
Damien Sendler: There is a lack of data on the risk variables that can be used to identify those at greater risk of SARS-CoV-2 reinfection. Older people, particularly those in long-term care institutions, immunocompromised patients, and those with specific comorbidities or exposure risk (e.g., health-care employees) may have greater rates of reinfections, although results remain inconclusive (Fakhroo et al., 2021; Hansen et al., 2021; Murillo-Zamora et al., 2021a, 2021b; Ringlander et al., 2021; Spicer et al., 2021). Reinfection risk may be influenced by exposure risk, which makes sense. Re-infection rates may rise if communities deploy fewer or no lockdown precautions and people are more confident in being exposed as a result of repeated exposures (Ioannidis, 2021a). As a result, the actual form of the exposure-reinfection risk function remains a mystery (e.g., if there is a plateau and many individuals will not get reinfected regardless of the amount of increasing exposure) Furthermore, distinguishing between COVID-19 persistence and re-infection is difficult, especially in the elderly (Ringlander et al., 2021). Re-infection risk may be influenced to some extent by the original severity of the SARS-CoV-2 infection as well. However, even asymptomatic SARS-CoV-2 infections cause an intense immune reaction (Boyton and Altmann, 2021; Garrido et al., 2021; Murillo-Zamora et al., 2021a; Schuler et al., 2021; Spicer et al., 2021).
It’s not clear whether testing for anti-SARS-CoV-2 antibodies in individuals with a history of infection may help determine their risk of relapse. Patients who had been previously infected with SARS-CoV-2 but had no detectable antibodies against the virus had an 80% protection rate (95 percent CI: 19%–95%) against SARS-CoV-2 infections, compared to a group of people who had never been infected with SARS-CoV-2 but had a negative serology (Breathnach et al., 2021a). Patients having a past SARS-CoV-2 infection did not have a higher risk of reinfection when compared to those without detectable anti-SARS-CoV-2 antibodies, according to the same research (Breathnach et al., 2021a). However, this data only raises doubts about the extra predictive utility of antibody measures in recovered patients, not the multiple studies demonstrating that persons with vs without detectable anti SARS-CoV-2 antibodies are at considerably decreased risk of infection (Harvey et al., 2021). Antibody testing is good, but incorporating it into recommendations for individualized healthcare is a risky or even dangerous move based on what we know so far. Antibody testing for clinical usage may exacerbate an already complicated environment in which viral testing is already extensive. This might exacerbate the sense of a persistent oddity in the population and lead to further misunderstandings.
Reinfection risk may also be influenced by other immunological responses. Strong cellular immune responses are also induced by SARS-CoV-2 infections (Havervall et al., 2022; Melenotte et al., 2020; Sekine et al., 2020). We need further research in this area to better understand how various kinds of cell-based immune responses, such as Th1 vs Th2, affect the likelihood of infection (Melenotte et al., 2020).
A strong humoral and cellular immune response is seen even in patients with moderate or asymptomatic SARS-CoV-2 infections, according to research (Kojima and Klausner, 2022). There have been many requests for measures of antibodies against SARS-CoV-2 during the COVID-19 pandemic, however these antibodies are only partial predictors of protection, and have not yet been established as part of a decision making process in most contexts. (Breathnach et al., 2021a; Kojima and Klausner, 2022). antibodies generated by SARS-CoV-2 infections are more varied with lower concentrations, yet they are focused not just against spike protein but many additional open reading frames encoded by 29,900 nucleotides of SARS-CoV-2, and also mucosal immune responses (Krammer, 2021). Cell-mediated responses to SARS-CoV-2 infections seem to be even more polyepitopic than the humoral response, with long-term maintenance of memory T- and B-cells in recovered patients (Milne et al., 2021; Turner et al., 2021).
When it comes to protecting against SARS-CoV-2 re-infections, it is important to note that the effectiveness of protection across multiple viral strains in 2020–2021 was nearly equal (Chemaitelly et al., 2021a; Kim et al., 2021). The Omicron variation, on the other hand, has a dearth of information as of the time of the writing of this article. SARS-CoV-2 infections produce an extensive immune response against the whole virus, therefore even future variations may not be able to totally elude natural immunity, according to this hypothesis. However, novel varieties (such as Omicron) often raise new problems that need a quick and accurate re-evaluation of our present understanding (Altarawneh et al., 2022; Christie, 2021; Del Rio et al., 2022; Kupferschmidt and Vogel, 2021). As vaccination rates rise and the global population is expected to have been infected with SARS-CoV-2 by the beginning of 2022, even if the vast majority of those infected have not been officially detected, it seems reasonable to assume that future outbreaks of SARS-CoV-2 infection, even if they are highly transmissible, will have a lower health impact. Omicron’s arrival demonstrates that even communities with very high past immunization rates and varying preceding infection rates may experience enormous spikes. The burden of hospitalizations and fatalities is, nevertheless, much lower than in 2020 and the first half of 2021. (Altarawneh et al., 2022; Christie, 2021; Kupferschmidt and Vogel, 2021; Ulloa et al., 2022). However, the real burden of Omicron infections must be extensively studied. The pandemic has already entered the endemic phase, and Omicron is an endemic wave happening in an environment where population immunity is widespread. This argument may be made in support of this hypothesis: There may be future endemic waves that are high-peaked, but if the clinical burden is low, this can be managed.
Conclusions from this study show a significant level of protection against re-infections and COVID-19 severe consequences from natural immunity established following SARS-CoV-2 infections. When compared to those who received just one mRNA dosage, the results are either equivalent or better. SARS-CoV-2 infection and immunization seem to be the most effective means of protecting against the disease. However, these findings must be taken in light of the limitations of our study, which was not based on a registered systematic review and meta-analysis, but rather aimed to update and expand the work of prior studies (Kojima et al., 2021; Petras, 2021; Shenai et al., 2021).
People should not intentionally get SARS-CoV-2 infection to avoid vaccination since it is linked with significant bad effects independent of the underlying variation of SARS-CoV-2 infection. Given the prevalence of past illnesses, it would be foolish to ignore them when making policy decisions. COVID-19 chances of catastrophic outcomes are lower in younger age groups, therefore this may be even more critical (Ioannidis, 2021b).
Natural immunity’s effectiveness and longevity are unquestionably significant for present and future policy considerations (Cheng et al., 2021; Dunkle et al., 2021; Gentile et al., 2021; Gupta et al., 2021; Ingram et al., 2021; Krause et al., 2021; Weinreich et al., 2021; Zemb et al., 2020). Natural immunity is yet to be fully understood, which presents a challenge to health policymakers and necessitates extra research efforts. Concerns about incorporating general population immunity into decisions on restrictions or other public health measures against SARS-CoV-2, as well as laboratory measures of protective immunity (e.g. antibody measurements or cellular immunity assays) that may have practical value for decision-making (and if so, in which settings) regarding vaccination or treatment of COVID-1 should be addressed. SARS-CoV-2 infection is expected to become a common occurrence within the next several years, if not sooner. It is critical to learn how to induce optimum hybrid immunity in previously infected individuals with SARS-CoV-2 by timing and technique of vaccination (including future improvements of vaccines).
