Quote” our review demonstrates that natural immunity in COVID-recovered individuals is, at least, equivalent to the protection afforded by full vaccination of COVID-naive populations. There is a modest and incremental relative benefit to vaccination in COVID-recovered individuals; however, the net benefit is marginal on an absolute basis. COVID-recovered individuals represent a distinctly different benefit-risk calculus. Therefore, vaccination of COVID-recovered individuals should be subject to clinical equipoise and individual preference. “

Abstract

BACKGROUND: We present a systematic review and pooled analysis of clinical studies to date, that (1) specifically compare the protection of natural immunity in the COVID-recovered versus the efficacy of full vaccination in the COVID-naive, and (2) the added benefit of vaccination in the COVID-recovered, for prevention of subsequent SARS-CoV-2 infection. METHODS: Using the PRISMA 2020 guidance, we first conducted a systematic review of available literature on PubMed, MedRxIV and FDA briefings to identify clinical studies either comparing COVID vaccination to natural immunity or delineating the benefit of vaccination in recovered individuals. After assessing for eligibility, studies were qualitatively appraised and formally graded using the NOS system for observational, case-control and RCTs. Incidence rates were tabulated for the following groups: never infected (NI) and unvaccinated (UV), NI and vaccinated (V), previously infected (PI) and UV, PI and UV. Pooling was performed by grouping the RCTs and observational studies separately, and then all studies in total. Risk ratios and risk differences are reported for individual studies and pooled groups, in 1) NPI/V vs. PI/UV and 2) PI/UV vs. PI/V analysis. In addition, number needed to treat (NNT) analysis was performed for vaccination in naive and previously infected cohorts. RESULTS: Nine clinical studies were identified including three randomized controlled studies, four retrospective observational cohorts, one prospective observational cohort, and a case-control study. The NOS quality appraisals of these articles ranged from four to nine (out of nine stars). All of the included studies found at least statistical equivalence between the protection of full vaccination and natural immunity; and, three studies found superiority of natural immunity. Four observational studies found a statistically significant incremental benefit to vaccination in the COVID-recovered individuals. In total pooled analysis, incidence in NPI/V trended higher than PI/UV groups (RR=1.86 [95%CI 0.77-4.51], P=0.17). Vaccination in COVID-recovered individuals provided modest protection from reinfection (RR=1.82 [95%CI 1.21-2.73], P=0.004), but the absolute risk difference was extremely small (AR= 0.004 person-years [95% CI 0.001-0.007], P=0.02). The NNT to prevent one annual case of infection in COVID-recovered patients was 218, compared to 6.5 in COVID-naive patients, representing a 33.5-fold difference in benefit between the two populations. CONCLUSIONS: While vaccinations are highly effective at protecting against infection and severe COVID-19 disease, our review demonstrates that natural immunity in COVID-recovered individuals is, at least, equivalent to the protection afforded by full vaccination of COVID-naive populations. There is a modest and incremental relative benefit to vaccination in COVID-recovered individuals; however, the net benefit is marginal on an absolute basis. COVID-recovered individuals represent a distinctly different benefit-risk calculus. Therefore, vaccination of COVID-recovered individuals should be subject to clinical equipoise and individual preference.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

No external funding was received.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This is a systematic review and metaanalysis, and therefore, does not need IRB approval.

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv