Hostname: page-component-5d59c44645-kw98b Total loading time: 0 Render date: 2024-03-04T23:06:47.984Z Has data issue: false hasContentIssue false

A systematic review of the evidence on the associations and safety of COVID-19 vaccination and post COVID-19 condition

Published online by Cambridge University Press:  18 August 2023

Sydney Jennings
Affiliation:
Public Health Risk Science Division, National Microbiology Laboratory, Public Health Agency of Canada, Guelph, ON, Canada Department of Population Medicine, University of Guelph, Guelph, ON, Canada
Tricia Corrin*
Affiliation:
Public Health Risk Science Division, National Microbiology Laboratory, Public Health Agency of Canada, Guelph, ON, Canada
Lisa Waddell
Affiliation:
Public Health Risk Science Division, National Microbiology Laboratory, Public Health Agency of Canada, Guelph, ON, Canada
*
Corresponding author: Tricia Corrin; Email: tricia.corrin@phac-aspc.gc.ca
Rights & Permissions [Opens in a new window]

Abstract

Post COVID-19 condition (PCC) refers to persistent or recurring symptoms (>8 weeks) occurring ≤12 weeks following acute COVID-19. The objective of this systematic review was to assess the evidence on the risk of PCC with vaccination before or after COVID-19 or after developing PCC, and the safety of vaccination among those already experiencing PCC. A search was conducted up to 13 December 2022 and standard systematic review methodology was followed. Thirty-one observational studies were included. There is moderate confidence that two doses of vaccine given pre-infection reduced the odds of PCC (pooled OR (pOR) 0.67, 95% CI 0.60–0.74, I2 = 59.9%), but low confidence that one dose may not reduce the odds (pOR 0.64, 95% CI 0.31#x2013;1.31, I2 = 99.2%), and the evidence is very uncertain about the effect of three doses (pOR 0.45, 95% CI 0.10#x2013;1.99, I2 = 30.9%). One of three studies suggested vaccination shortly after COVID-19 may offer additional protection from developing PCC compared to unvaccinated individuals, but this evidence was very uncertain. For those with PCC, vaccination was not associated with worsening PCC symptoms (10 studies) and appears safe (3 studies), but it is unclear if vaccination may change established PCC symptoms.

Type
Review
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - ND
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-nc-nd/4.0), which permits non-commercial re-use, distribution, and reproduction in any medium, provided that no alterations are made and the original article is properly cited. The written permission of Cambridge University Press must be obtained prior to any commercial use and/or adaptation of the article.
Copyright
© His Majesty the King in Right of Canada, as represented by the Minister of Health, 2023. Published by Cambridge University Press

Introduction

Individuals who have been infected with SARS-CoV-2 may continue to experience persistent symptoms beyond the acute phase of COVID-19 disease. The World Health Organization (WHO) defines post COVID-19 condition as persistent symptoms occurring 12 or more weeks after an acute COVID-19, which have persisted or re-occurred for a minimum of eight weeks and cannot be explained by alternative diagnoses [1]. Many studies also report on post-acute sequelae (PAS) during the period immediately following acute infection from 4 to 12 weeks post-diagnosis [Reference Nalbandian2]. The predominant symptoms experienced with PCC include fatigue, dyspnea (shortness of breath), other respiratory issues, cardiovascular issues, pain, sleep disturbances, decrease in quality of life, cognitive impairment, and anxiety or depression [1, 3, Reference Domingo4].

The variability in what defines sequelae following COVID-19, including the range of reported symptoms and durations, has made true case counts difficult to ascertain; however, the burden of PCC has been estimated to affect approximately 10-20% of individuals following COVID-19 [Reference Quinn5, 6]. Higher proportions (more than 50%) have been reported for those with at least one symptom related to PCC beyond 12 weeks after infection in studies of hospitalised cases that had severe COVID-19 [Reference Domingo4]. Following the COVID-19 vaccine rollout in 2021, more than 13.3 billion vaccine doses have been administered globally as of 24 February 2022 [7]. Given the high estimated burden of PCC, it is important to assess the global evidence of the impact of COVID-19 vaccination on PCC, including potential benefits and/or safety concerns.

A few systematic reviews investigating the impact of COVID-19 vaccination on PCC have been completed to date and have all included outcomes on PAS [Reference Gao, Liu and Liu8Reference Marra11]. This review addresses the impact of vaccination on only PCC and extends included outcomes to all options for the timing of vaccination relative to infection and/or PCC (pre-infection, post-infection, and post PCC) and provides an updated synthesis of the rapidly evolving literature. Assessing the evidence related to only PCC may reduce the heterogeneity in results. Therefore, the objective of this systematic review (SR) and meta-analysis was to assess the global evidence on the associations and safety of COVID-19 vaccination and PCC (symptoms >12 weeks from infection) through the following questions: Does COVID-19 vaccination 1) before or 2) after COVID-19 decrease the risk of developing PCC?; 3) Among those who already have PCC, does subsequent COVID-19 vaccination change their symptoms?; and 4) Is it safe to get a COVID-19 vaccine for individuals who have PCC?

Methods

This SR adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was conducted following standard SR methods outlined by the Cochrane Collaboration [Reference Liberati12, Reference Higgins13]. A protocol outlining the SR question and methodology was determined a priori and registered in PROSPERO (CRD42022365386). All deviations from the original protocol, mainly additional information extracted, have been noted in the updated protocol document in PROSPERO.

Research question and eligibility criteria

The research questions of this SR were as follows: 1) Does COVID-19 vaccination before COVID-19 decrease the risk of developing PCC or the risk of developing specific PCC symptoms?; 2) Does COVID-19 vaccination after COVID-19 decrease the risk of developing PCC or the risk of developing specific PCC symptoms?; 3) Among those that already have PCC, does COVID-19 vaccination lead to symptom changes?; and 4) Is it safe to get a COVID-19 vaccine for individuals who have PCC?

We followed a universal case definition of PCC, in accordance with the World Health Organization (WHO), defined as persistent symptoms occurring 12 or more weeks after acute COVID-19, which persist or reoccur for a minimum of eight weeks [1]. The population of interest was anyone who had COVID-19. All age groups were considered for inclusion, and children and elderly were summarised separately, where possible. The intervention was vaccination (analysis to be sub-grouped by number of doses) with any type of authorised COVID-19 vaccine, and vaccination could occur before or after COVID-19 or after developing PCC. The comparison group was unvaccinated individuals who had COVID-19 or comparison between doses of COVID-19 vaccination among those who had COVID-19. The primary outcomes of interest were the risk of developing PCC or resolution of PCC, and secondary outcomes were measurements of development of individual symptoms associated with PCC, changes to PCC symptoms among those with PCC, and adverse events following COVID-19 vaccination among those with PCC depending on the research question being assessed. Both published and preprint primary research studies with an observational or experimental study design were considered for inclusion, and preprint studies were continuously monitored for the availability of a published version.

Studies were excluded from the systematic review if they were not primary research, that is, did not present data collected by the author. Descriptive studies (i.e., case reports or case series), studies only assessing antibody responses to vaccination among individuals with PCC, predictive modelling studies, and studies only assessing changes in symptoms among vaccinated individuals with PCC with no comparator group were excluded. Studies were also excluded if they only examined people with PAS or if the sample included those with PAS and PCC where the results specific to PCC could not be extracted; a list of excluded studies is in Supplementary Table S1.

Search strategy

A database of COVID-19 literature has been continuously curated since February 2020 within the agency [Reference Corrin14]. Updates were conducted daily until May 2022 and twice per week up to the search date. A COVID-19 search algorithm was adapted to and implemented in the following databases: PubMed, Scopus, and preprint servers BioRxiv, MedRxiv, ArXiv, SSRN, and Research Square, which were searched via EuropePMC since June 2022. Full scan results are maintained in a bibliographic management software Endnote and searchable Excel line lists. The search algorithm for this SR was run within the Endnote database with no restrictions on language and included a combination of PCC OR non-specific symptom terms AND vaccination terms (see protocol for details). The search was conducted on 21 September 2022 and updated on 13 December 2022.

Search verification

The reference lists of five relevant review articles were searched as part of search verification [Reference Gao, Liu and Liu8Reference Byambasuren10, Reference Bauernfeind and Schmidt15, Reference Mumtaz16]. This process yielded two studies that were subsequently included within the screening process [Reference Hajjaji17, Reference Zisis18].

Study selection and data extraction

The search results were imported into EndNote20 (Clarivate, Philadelphia, PA) and de-duplicated. Unique references were imported into DistillerSR software (DistillerSR. Version 2.35. DistillerSR Inc.; 2022) for systematic review management. Title/abstract and full-text relevance screening forms and a data extraction form were developed a priori and piloted by all three reviewers to determine functionality. Title/abstract and full-text screening were performed in duplicate by two independent reviewers. Study characterisation and data extraction of relevant articles were also performed in duplicate by two independent reviewers and included publication details (e.g., language, year), funding and conflict of interest, study design, sample location and sampling frame, study period, population characteristics (e.g., demographics, COVID-19 severity), vaccination information (e.g. number of doses, vaccine product/brand received, additionally relevant details such as sample size per treatment group), time to outcome assessment, outcome measurement/ diagnostic tools used, and outcome data. Conflicts at each stage of screening and data extraction were resolved by consensus or by a third reviewer, where necessary. Upon publication of a previously captured preprint, the publication was updated and re-evaluated to make sure all extracted data and risk of bias assessment reflected the most up-to-date version of the article.

Risk of bias assessment

The articles included in this SR were evaluated for their risk of bias (ROB) using the Newcastle–Ottawa Scale (NOS) [Reference Wells19], which was selected over the Risk Of Bias In Non-randomised Studies of Interventions because, while both are commonly used, NOS is more efficient and easier to implement, and the relationship between COVID-19 vaccination and development or remissison of PCC may not be a direct relationship [Reference Sterne20]. Two pre-existing NOS forms for case–control and cohort studies were used as well as a modified tool for cross-sectional studies to perform the ROB assessment [Reference Ribeiro21]. The ROB was assessed in duplicate by two independent reviewers. Across tools some of the specific questions differed by study design, but generally assessed possible selection bias (e.g., inappropriate or non-representative sampling frame), information bias (e.g., misclassification or inadequate measurement of variables), confounding bias (e.g., inadequate consideration or control of possible confounding variables), and/or reporting bias (e.g., insufficient reporting of key details to allow possible replication and informed inferences). Each tool was pretested on one article by all reviewers prior to proceeding with independent assessment of the remaining articles by two reviewers. Conflicts were resolved through discussion and consensus.

Data synthesis

The complete dataset was exported into Microsoft Excel (2016), where results were grouped according to the review question addressed, and tabulated to summarise the primary and secondary outcomes, and any moderating variables identified that may change the association between vaccination and PCC outcomes. Narrative synthesis of the data for each review question was performed. We expected a priori that there would be high heterogeneity between studies due to variability in study design, sample, timing of the study, vaccination, time since last vaccine, and measurement of the outcome, despite restricting the review to PCC outcomes at 12 or more weeks and sub-grouping by number of vaccine doses. When there were two or more studies measuring the same association for a main outcome, random-effects meta-analyses using the restricted maximum likelihood estimator for between-study variance were developed using STATA17 (StataCorp 2021) sub-grouped by number of COVID-19 vaccination doses received and the reported outcome measures. The sub-group meta-analyses allow the reader to visualise the precision of individual studies measuring the same association and agreement across studies coupled with a GRADE assessment of the certainty of the evidence. For meta-analysis, risk ratios (RR) and prevalence ratios (PR) were converted to odds ratios (OR) to calculate a pooled effect (pOR) [Reference Zhang and Yu22, Reference Carazo23]. Hazard ratios (HR) and incidence rate ratios (IRR) were pooled together but kept separate from ORs because HRs and IRRs measure rate of change over a defined period, whereas OR and RR report the associations across the entire study period, and thus their meaning and value are different [Reference George, Stead and Ganti24]. The impact of risk of bias (low, moderate, high) was examined for outcomes considered for meta-analysis. Testing for small study effects was only considered where meta-analyses included more than ten observations/lines of data; none of the analyses met this criterion. As part of the sensitivity analysis for meta-analysis sub-groups with more than three studies, the Hartung-Knapp-Sidik-Jonkman method for estimating more conservative confidence intervals was examined and reported in Supplementary Table S2 [Reference IntHout, Ioannidis and Borm25], and the prediction intervals were calculated to provide a plausible range of effect size in a future, new study and reported in Table 2 and Supplementary Table S2 [Reference IntHout26].

Certainty of evidence

Grading the quality of evidence and the strength of recommendations (GRADE) criteria are summarised across groups of similar studies and the GRADE framework was applied to indicate the level of confidence in the current evidence for the main outcomes of development or resolution of PCC [Reference Schünemann27]. The GRADE domain’s risk of bias, inconsistency, imprecision, indirectness, and dose response were evaluated to determine a one- to four-star grade. Given the expected observational study designs, higher risk of bias, and heterogeneity, GRADE ratings were expected to be very low to low for most outcomes unless there were consistent results across several large studies for an outcome; details of the evaluation scheme are available in the GRADE guide (Supplementary Table S2). The grading system indicates the following: ****high confidence that the effect estimate is close to the true effect; ***moderate confidence in the effect estimate, but future studies may be substantially different; **limited confidence in the estimate of effect, the true effect may be substantially different; and *very little confidence in the estimate of effect, the true effect is likely to be substantially different. The outcomes with one study resulted in a very little confidence rating. A summary of findings table including the GRADE for the main outcomes is available in Table 2.

Results

Study selection

There were 1,367 citations screened for relevance, 101 potentially relevant citations underwent full-text screening, and 31 have been included in this SR: 24 peer-reviewed research articles, 5 preprints, one letter to the editor, and one short communication (Figure 1 and Supplementary Tables S3–S6). Articles that only assessed PAS (n = 22), or that did not differentiate between study participants with PAS and PCC (n = 12), as well as studies that did not report the timing of vaccination (n = 8) were excluded (Supplementary Table S1).

Figure 1. PRISMA flow diagram of articles through the systematic review process.

Characteristics of the included studies

The included studies addressed the association and/or safety of COVID-19 vaccination and PCC according to the following subtopics: the effect of vaccination administered 1) before (n = 18) or 2) after (n = 3) COVID-19; 3) among previously unvaccinated individuals already experiencing PCC (n = 10); and 4) adverse events post-vaccination among those with PCC (n = 3). All studies had an observational study design (prospective cohort, n = 16; retrospective cohort, n = 5; cross-sectional, n = 9; case–control, n = 1) and had high (n = 17), moderate (n = 13), and low (n = 1) risk of bias (Table 1). None of the studies were funded by the pharmaceutical industry, and none of the authors declared conflicts of interest (Supplementary Tables S3–S6). Most studies were conducted in Europe (n = 18) or North America (n = 7), and two had a multi-national sampling frame. More than half (n = 22) assessed individuals with mixed severities of COVID-19. Two studies reported on elderly populations, and no studies reported on children. Vaccine products received were mostly BNT162b2 (Pfizer-BioNTech, Comirnaty, n = 21) and mRNA-1273 (Moderna, Spikevax, n = 14). More than half of the studies (n = 23) included individuals who had received two doses of a COVID-19 vaccine, and six studies included individuals vaccinated with three doses.

Table 1. General characteristics of the 31 included primary research publications on post COVID-19 condition and vaccination, grouped by research questiona

a Each group may sum to >31 because studies can be included in more than one category and more than one question.

(Q1) Risk of developing PCC in those vaccinated before COVID-19

The association between PCC and COVID-19 vaccination before COVID-19 was assessed in 18 studies, including 9 prospective cohorts, 5 retrospective cohorts, 1 case-control study, and 3 cross-sectional studies (Table 1). Fifteen studies stratified their analyses by dose-specific vaccination status (one dose, n = 4; two doses, n = 11; three doses, n = 3) (Supplementary Table S3) and 12 contributed to the meta-analyses (Figures 2 and 3) [Reference Carazo23, Reference Al-Aly, Bowe and Xie28Reference Taquet, Dercon and Harrison38].

Figure 2. Meta-analysis of the effect of vaccination prior to COVID-19 compared to unvaccinated on the odds of developing PCC, stratified by number of doses.

Figure 3. Meta-analysis of the hazard ratios for developing PCC in those vaccinated prior to COVID-19 compared to unvaccinated, stratified by number of doses.

Twelve studies reported the main outcome of developing PCC, as shown in Table 2. These results were pooled by number of doses; each sub-group was assessed for the certainty of evidence, and an illustrative example of the reduction in cases with vaccination was calculated using a baseline of 25% of unvaccinated Canadians report suffering from PCC after COVID-19 [39]. There is moderate to high heterogeneity across studies in each meta-analysis sub-group, which suggests that the pooled associations should be used with caution; however, there are few studies for most outcomes so there is limited exploration of heterogeneity. One dose of vaccine prior to COVID-19 may not reduce the odds of developing PCC compared to unvaccinated individuals across four studies (pOR 0.64, 95% CI 0.31 – 1.31, four studies) with high heterogeneity (I2 = 99.2%) (Figure 2).

Table 2. Summary of findings table for the main outcomes of PCC development or remission. Separated by odds ratios/hazard ratios, number of vaccine doses, and type of vaccine

Note: The illustrative example is based on a PCC prevalence of 25% in the unvaccinated population. For explanations see the GRADE data in Supplementary Table S2.

Abbreviations: aHR, adjusted HR; aIRR, adjusted incidence rate ratio; aOR, adjusted OR; CI, confidence interval; GRADE, grade of evidence; HR, hazard ratio; OR: odds ratio; pHR: pooled HR; pOR: pooled odds ratio.

*The basis for the assumed risk was a base rate of 25.0% (95%CI 21.5–28.8) reported by unvaccinated Canadians and 13.2% (11.3–15.3%) for those with two doses of COVID-19 vaccine up to 31 August 2022 in the Canadian COVID-19 Antibody and Health Survey [39]. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the intervention group and the relative effect of the intervention (and its 95% CI). GRADE, grade of evidence based on a four-star scale of **** high confidence to * very low confidence in the evidence.

Two doses of vaccine prior to COVID-19 likely reduced the odds of developing PCC compared to unvaccinated individuals (pOR 0.67, 95% CI 0.60–0.74, I2 = 59.9%, five studies) with a 95% prediction interval of 0.49–0.90 indicating a protective association would likely be present in a future study (Figure 2). A sixth study that combined those with one and two doses aligned with the two-dose analysis (pOR 0.49, 95% CI 0.31–0.79). Across four studies reporting hazard ratios, one or two doses of vaccine prior to COVID-19 may have little to no effect on the average hazard of developing PCC up to a six-month follow-up, but the evidence was very uncertain (HR one dose 0.96, 95% CI 0.89–1.03; pHR two doses 0.81, 95% CI 0.67–0.98, I2=96.6%, four studies) (Figure 3). In the two-dose hazard ratio analysis, the two studies reporting a reduction in the hazard of PCC were at moderate risk of bias and the others were at high risk of bias; however, this did not explain a lot of the between-study heterogeneity (Table 2). Further sensitivity analysis indicated that the removal of Brannock et al. resulted in an estimate of no association, and the 95% prediction interval was wide (0.39–1.69) suggesting the results were imprecise [Reference Brannock31]. Sensitivity analyses of the other outcomes indicated no individual study had a large impact on the meta-analysis as the removal of each study did not alter the significance or direction of the meta-analysis. The evidence is very uncertain for the effect of three doses of vaccine prior to COVID-19 on the odds (pOR 0.45, 95% CI 0.10–1.99, I2= 30.9%) of developing PCC in one small underpowered study that reported observations separately for Delta and Omicron infections (Figure 2) [Reference Ballouz30]. In this study, a reduced odds of PCC was reported for people with three doses when Omicron was circulating, but there were too few observations when Delta was circulating to detect an association.

The nine studies that reported data on the impact of vaccination prior to COVID-19 on individual PCC symptoms were heterogeneous across the studies. In some studies vaccination was associated with a lower odds of common PCC symptoms including anxiety/depression in 3/5 studies, fatigue in 2/4 studies, dyspnea in 2/4 studies, and change/loss of smell in 1/3 studies (Supplementary Table S3). No association was found with headache in 2/2 studies and no studies reported associations with worse symptoms among those vaccinated compared to the unvaccinated. There was a reduced incidence rate of several PCC symptoms among those with three versus two doses up to four months post Omicron infection (physical symptoms: IRR 0.91, 95% CI 0.88–0.94, depression: 0.82, 0.77 – 0.88, anxiety; 0.84, 0.80–0.89, fatigue: 0.95, 0.93–0.97, and cognitive complaints: 0.91, 0.88–0.94) [Reference Spiliopoulos40]. There was no association between one to three vaccine doses before infection and the number of PCC symptoms reported (aRR 1.27, 95% CI 0.82–1.94) compared to the unvaccinated [Reference Kahlert41].

Two studies addressed differences between vaccine products, and both showed that all vaccine products reduced the risk of developing PCC. One showed that mRNA vaccines resulted in a decreased risk of PCC compared to Ad26.COV2.S (Johnson & Johnson) (aHR 0.89, 95% CI 0.81–0.97) [Reference Al-Aly, Bowe and Xie28], while the other found no significant difference between mRNA (BNT162b2 and mRNA-1273) and ChAdOx1 (AstraZeneca) vaccines [Reference Ayoubkhani42]. The timing of vaccination before infection was assessed in three studies. One small study found that vaccination (one to three doses) within six months of Omicron infection was associated with a lower odds of PCC compared to those vaccinated more than six months before Omicron infection, but time of last vaccine before Delta infection was not associated with the odds of developing PCC [Reference Ballouz30].

One study stratified their analysis by age groups (<60 and >60 years old); however, no significant difference in the hazard of developing PCC was found between the age groups compared and the unvaccinated groups [Reference Taquet, Dercon and Harrison38]. None of the studies reported a different association or interaction between males and females and vaccination prior to COVID-19 and the risk of developing PCC.

(Q2) Risk of developing PCC in those vaccinated after acute COVID-19

Three studies assessed the association between PCC and vaccination post-infection (up to 12 weeks post COVID-19), including one prospective cohort, one retrospective cohort, and one cross-sectional study (Supplementary Table S4). These studies included participants vaccinated with one dose (n = 1), two doses (n = 1), or one or two doses (n = 1) of COVID-19 vaccines.

Only one study established vaccination post-infection was administered prior to PCC development. The protective effect was stronger when one dose of vaccine was given earlier post-infection (aOR 0–4 weeks post-infection 0.38, 95% CI 0.35–0.41; aOR 4–8 weeks post-infection 0.54, 95% CI 0.51–0.57; aOR 8–12 weeks post-infection 0.75, 95% CI 0.71–0.78) compared to the unvaccinated (Table 2) [Reference Simon, Luginbuhl and Parker37].

Vaccination prior to PCC development was not clearly established in the other two studies. One study found no difference in cognition, grey matter volume, white matter hyperintensities, or functional connectivity between those with one or two doses of vaccine versus the unvaccinated, but vaccinated individuals performed better on visual, object, and space perception battery discrimination [Reference Diez-Cirarda43]. The third study found no difference in the rate of PCC at the six-month follow-up in those vaccinated with two doses post- versus pre-infection (aIRR 0.91, 95% CI 0.75–1.10) (Table 2) [Reference Jassat35].

(Q3) Changes in PCC following vaccination among individuals with established PCC

Ten studies looked at the effect of COVID-19 vaccination on individuals with PCC (prospective cohort, n = 7; cross-sectional, n = 3). Follow-up times were between 3 and 14 months post-infection and 0.5–6 months post-vaccination with one (n = 10) or two doses (n = 5). Except for two studies, most were completed in early 2021 at the beginning of the vaccine rollout (Supplementary Table S5).

Among seven studies that compared vaccinated and unvaccinated individuals with established PCC [Reference Arnold44Reference Suyanto50], three studies addressed the main outcome of PCC resolution following one dose, two of which did not demonstrate an association [Reference Wynberg46, Reference Nehme49] and the third reported double the remission rate among vaccinated individuals [Reference Tran45] (Table 2). Three studies compared self-reported outcome data pre- and post-vaccination, all of which found beneficial outcomes after the first dose [Reference Ayoubkhani42, Reference Strain51, Reference Krishna52]. Individuals were more likely to experience symptom improvement after vaccination in two studies [Reference Strain51, Reference Krishna52], and the third study found the odds of PCC were slightly reduced following both the first (OR 0.87, 95% CI 0.81–0.93) and second doses (OR 0.91, 95% CI 0.86–0.97) [Reference Ayoubkhani42]. Despite an apparent improvement, one study reported that 50% of the respondents who had reduced or worsened symptoms following vaccination returned to pre-vaccination levels within three weeks [Reference Strain51]. Other studies reported on mean difference in symptoms or composite symptom score [Reference Arnold44, Reference Wisnivesky47, Reference Krishna52] – proportions of those reporting improved, worsened, or no symptom changes [Reference Peghin48, Reference Strain51] – or various quality of life scores [Reference Arnold44, Reference Suyanto50] and were inconsistent in finding an association with one dose of vaccine.

Five studies reported on two doses of vaccine post-infection, of which two studies found no significant differences in any PCC symptoms after one or two doses [Reference Wisnivesky47, Reference Peghin48]. One showed an incremental benefit to the second dose after the first dose [Reference Ayoubkhani42], and two studies found that two doses was a significant predictor for a better quality of life score [Reference Suyanto50] and was significantly protective against persistent PCC symptoms compared to no vaccination (Table 2) [Reference Nehme49]. The latter study also stratified by age and sex finding that only elders (≥60 years) who received two doses post-infection had significantly lower odds of persistent PCC (but not younger individuals) and males and females had an equally lower odds of persistent PCC after two doses post-infection.

Seven studies reported changes to individual symptoms following vaccination [Reference Ayoubkhani42, Reference Arnold44, Reference Wisnivesky47-Reference Nehme49, Reference Strain51, Reference Krishna52], two of which did not report extractable quantitative data [Reference Arnold44, Reference Krishna52]. Few studies reported that vaccinated individuals had significant improvements in specific symptoms including fatigue in 2/5 studies, loss of smell in 1/4 studies, dyspnea in 1/5 studies, and other symptoms not associated with vaccination (Supplementary Table S5).

Four studies compared mRNA and adenoviral vector vaccines, three of which found no significant differences between participants who received mRNA vaccines (BNT162b2 or mRNA-1273) and adeno-viral vector vaccines (ChAdOx1 or Ad26.COV2.S) [Reference Ayoubkhani42, Reference Arnold44, Reference Peghin48]. However, one study suggested mRNA-1273 reduced some PCC symptoms significantly better than ChAdOx1 including fatigue, brain fog, myalgia, gastro-intestinal symptoms, and autonomic dysfunction [Reference Strain51].

(Q4) Safety and risk of adverse events following COVID-19 vaccination among individuals with PCC

Three studies reported on the safety or adverse events among those with PCC following COVID-19 vaccination, all of which included participants following one dose of a COVID-19 vaccine (Supplementary Table S6). Only one study included a comparator group of individuals vaccinated with no history of COVID-19 and found no significant difference in the number or type of side effects following one dose of a vaccine (BNT162b2) among those with PCC compared to controls [Reference Raw53]. The study concluded that having a history of COVID-19, but not PCC, was associated with an increased risk of adverse events following vaccination. However, only a small subset of the study participants (n = 30/944) had reported experiencing PCC. A large prospective cohort study also found that COVID-19 vaccination was safe in individuals with PCC, finding that only 5.7% (n = 26/455) of participants self-reported adverse events post-vaccination (ChAdOx1, BNT162b2, mRNA-1273, or Ad26.COV2.S) [Reference Tran45]. However, the control group was those with PCC that were unvaccinated, so no statistical analysis was performed to support the finding that the effects of vaccination were like those without PCC. Lastly, in a small survey of 67 healthcare workers experiencing PCC, 72% (n = 48) reported immediate, but self-limiting side effects at two weeks post-vaccination (BNT162b2) [Reference Gaber54].

Discussion

The results of this SR are aligned with other evidence syntheses completed on this topic to date, which have agreed that vaccination administered before COVID-19 confers some protection against the risk of developing PCC [Reference Gao, Liu and Liu8Reference Marra11]. The evidence for a protective association with vaccination was most consistent, moderate certainty, when two doses of vaccine were received prior to COVID-19, suggesting a decreased odds of PCC by 33% compared to the unvaccinated. Vaccination shortly following COVID-19 may offer additional protection against developing PCC compared to no vaccination, but the evidence was very uncertain from only one study. Vaccination was not associated with a higher risk of developing PCC or worsening PCC symptoms in any study.

This SR restricted inclusion to only studies addressing PCC (symptoms still present >12 weeks from infection), but also included a wider range of results according to the timing of vaccination (i.e., pre-infection, post-infection, and post development of PCC) compared to other syntheses. Most of the reviews conducted to date have included PAS outcomes measured in the post-acute phase of COVID-19 at 4-12 weeks after infection, which may provide different associations with vaccination compared to studies of PCC [Reference Gao, Liu and Liu8Reference Marra11].

As part of the updated evidence included in this SR, preliminary evidence on the effect of three or more doses and SARS-CoV-2 variants were identified [Reference Ballouz30, Reference Jassat35, Reference Spiliopoulos40, Reference Kahlert41]. A third dose of a COVID-19 vaccine may offer additional protection against PCC, however in the two versus three dose analyses, it is unclear whether the additional protection is due to the shorter time between the last vaccine dose received and COVID-19 [Reference Ballouz30]. Vaccination also appeared to be more protective against PCC in individuals post Omicron infection compared to Delta in some studies [Reference Ballouz30, Reference Kahlert41]. However, the lack of significant findings within Delta-infected groups may also be due to sample size limitations as the vaccine rollout of dose 1 and 2 was underway and booster doses were not widely available prior to the surge in Delta cases.

Vaccination prior to COVID-19 that does not prevent infection has been shown to be associated with reduced severity of infection due to established immune response, which may also be the basis for a reduced risk of developing PCC, but vaccination post-infection may not have this benefit. Only one study directly addressed vaccination 0–12 weeks post COVID-19 diagnosis and reported a more protective association against PCC when the first dose was given closer to infection [Reference Simon, Luginbuhl and Parker37]. This paucity of evidence about post-infection vaccination was not surprising given that vaccination closely following COVID-19 was not consistent with public health guidance.

Vaccination following diagnosis with PCC was safe in a few studies from early in vaccine rollout. However, the evidence was uncertain on whether vaccination may reduce PCC symptoms or result in faster resolution of symptoms. Most studies only assessed symptom changes following the first dose, and follow-up time may not have been sufficient to establish temporary versus permanent relief of symptoms post-vaccination. Some of the variability may be the result of self-reported outcome assessments that may be at high risk of recall bias.

Few studies examined interaction of sociodemographic variables on the association of PCC and vaccination. Factors such as sex, age, and severity of initial COVID-19 have been reported as risk factors for PCC [Reference Emecen32, Reference Hastie33, Reference Nascimento36] and were controlled for in many of the included studies. Any differences would be important to consider when developing treatment recommendations and equitable resource allocation. Finally, no study looked at the effect of vaccination on PCC given multiple COVID-19s. As the pandemic continues, re-infection is increasingly common and may compound the risk of PCC [Reference Bowe, Xie and Al-Aly55]. Understanding the role of vaccination against PCC given multiple infections is therefore extremely important.

Many of the limitations in synthesising the included studies relate to methodological differences for how PCC was defined and classified. For example, prospective studies often relied on self-reported data while retrospective studies looked at electronic health records and ICD-10 codes, both of which could have resulted in the misclassification of PCC due to sequelae that are actually related to other conditions. In addition, variable reporting of PCC symptoms made it difficult to compare across studies. Research and development of validated tools and diagnostics for PCC will be critical to improving our understanding and management of this condition.

Some limitations regarding our SR process include the fact that this SR explores a rapidly evolving topic and while an updated search was conducted on 13 December 2022, it is likely that the evidence has continued to evolve, and the findings of this SR may change with emerging evidence. The risk of bias assessment of the included observational studies used the NOS tool, for which a publication describing its validation is still forthcoming and an adaptation of the tool for cross-sectional study designs was used [Reference Ribeiro21].

Conclusion

From the evidence included in this SR, there is moderate confidence that having two or more doses of COVID-19 vaccines prior to COVID-19 reduces the odds of developing PCC. For those with PCC, getting a COVID-19 vaccine appears to be safe, but it is unclear if vaccination improves PCC symptoms that have already developed. Given the high case counts of COVID-19 and the high estimated burden of PCC, it is expected that the COVID-19 pandemic will have substantial health impacts beyond acute infection. Understanding the impact of vaccination on PCC therefore has important implications for practice and policy.

Supplementary material

The supplementary material for this article can be found at https://doi.org/10.1017/S0950268823001279.

Data availability statement

The data that support the findings of this study are openly available in Supplementary Tables S1–S6.

Author contribution

Conceptualization: L.A.W.; Data curation: L.A.W., S.J., T.C.; Formal analysis: L.A.W., S.J., T.C.; Investigation: L.A.W., S.J., T.C.; Methodology: L.A.W., S.J., T.C.; Project administration: L.A.W., S.J., T.C.; Supervision: L.A.W., T.C.; Validation: L.A.W., S.J., T.C.; Writing – original draft: L.A.W., S.J.; Writing – review & editing: L.A.W., S.J., T.C.

Competing interest

The authors declare none.

References

World Health Organization (2021) A clinical case definition of post covid-19 condition by a delphi consensus. Geneva: World Health Organization, 6 October 2021. Report No: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1.Google Scholar
Nalbandian, A, et al. (2021) Post-acute covid-19 syndrome. Nature Medicine 27, 601615. https://doi.org/10.1038/s41591-021-01283-zCrossRefGoogle ScholarPubMed
Government of Canada. Post covid-19 condition (long covid). Available at https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/symptoms/post-covid-19-condition.html (accessed 14 September 2022).Google Scholar
Domingo, FR, et al. (2021) Prevalence of long-term effects in individuals diagnosed with covid-19: An updated living systematic review. medRxiv. Epub June 3, 2021. https://doi.org/10.1101/2021.06.03.21258317CrossRefGoogle Scholar
Quinn, KL, et al.(2022) Understanding the post covid-19 condition (long covid) in adults and the expected burden for Ontario. The Ontario COVID-19 Science Advisory Table. Epub September 7, 2022. https://doi.org/10.47326/ocsat.2022.03.65.1.0CrossRefGoogle Scholar
Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. Covid-19 dashboard. Available at https://coronavirus.jhu.edu/map.html (accessed 20 November 2022).Google Scholar
Gao, P, Liu, J and Liu, M (2022) Effect of covid-19 vaccines on reducing the risk of long covid in the real world: A systematic review and meta-analysis. International Journal of Environmental Research and Public Health; 19, 12422. https://doi.org/10.3390/ijerph191912422CrossRefGoogle ScholarPubMed
Notarte, KI, et al. (2022) Impact of covid-19 vaccination on the risk of developing long-covid and on existing long-covid symptoms: A systematic review. eClinicalMedicine 53, 101624. https://doi.org/10.1016/j.eclinm.2022.101624CrossRefGoogle ScholarPubMed
Byambasuren, O, et al. (2023) Effect of covid-19 vaccination on long covid: Systematic review. BMJ Medicine 2, e000385. https://doi.org/10.1136/bmjmed-2022-000385CrossRefGoogle ScholarPubMed
Marra, AR, et al. (2022) The effectiveness of coronavirus disease 2019 (covid-19) vaccine in the prevention of post–covid-19 conditions: A systematic literature review and meta-analysis. Antimicrobial Stewardship & Healthcare Epidemiology 2, e192. https://doi.org/10.1017/ash.2022.336CrossRefGoogle ScholarPubMed
Liberati, A, et al. (2009) The prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Journal of Clinical Epidemiology 62, e1e34. https://doi.org/10.1016/j.jclinepi.2009.06.006CrossRefGoogle ScholarPubMed
Higgins, JPT, et al. Cochrane handbook for systematic reviews of interventions version 6.3: Cochrane. Available at www.training.cochrane.org/handbook (accessed September 2022).Google Scholar
Corrin, T, et al. (2023) Covid-19 literature surveillance—A framework to manage the literature and support evidence-based decision-making on a rapidly evolving public health topic. Canada Communicable Disease Report 49, 59. https://doi.org/10.14745/ccdr.v49i01a02CrossRefGoogle ScholarPubMed
Bauernfeind, S and Schmidt, B (2022) The value of covid-19 vaccination in the context of long-covid. Die Innere Medizin; 63, 840850. https://doi.org/10.1007/s00108-022-01368-yCrossRefGoogle ScholarPubMed
Mumtaz, A, et al. (2022) Covid-19 vaccine and long covid: A scoping review. Life 12, 1066. https://doi.org/10.3390/life12071066CrossRefGoogle ScholarPubMed
Hajjaji, N, et al. (2022) 16 months follow up of patients’ behavior and mild covid-19 patterns in a large cohort of cancer patients during the pandemic. Frontiers in Oncology 12, 901426. https://doi.org/10.3389/fonc.2022.901426CrossRefGoogle Scholar
Zisis, SN, et al. (2022) The protective effect of coronavirus disease 2019 (covid-19) vaccination on postacute sequelae of covid-19: A multicenter study from a large national health research network. Open Forum Infectious Diseases 9, ofac228. https://doi.org/10.1093/ofid/ofac228CrossRefGoogle ScholarPubMed
Wells, GA, et al. The Newcastle-Ottawa Scale (nos) for assessing the quality of nonrandomised studies in meta-analyses. Available at https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed 14 September 2022).Google Scholar
Sterne, JA, et al. (2016) Robins-i: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355, i4919. https://doi.org/10.1136/bmj.i4919CrossRefGoogle ScholarPubMed
Ribeiro, CM, et al. (2020) Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity: A systematic review and meta-analysis. BMJ Open 10, e033509. https://doi.org/10.1136/bmjopen-2019-033509CrossRefGoogle ScholarPubMed
Zhang, J and Yu, KF (1998) What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. Journal of the American Medical Association 280, 16901691. https://doi.org/10.1001/jama.280.19.1690CrossRefGoogle ScholarPubMed
Carazo, S, et al. (2022) Physical, psychological and cognitive profile of post-covid condition in healthcare workers, Quebec, Canada. Open Forum Infectious Diseases 9, ofac386. https://doi.org/10.1093/ofid/ofac386CrossRefGoogle Scholar
George, A, Stead, TS and Ganti, L (2020) What’s the risk: Differentiating risk ratios, odds ratios, and hazard ratios? Cureus 12, e10047. https://doi.org/10.7759/cureus.10047.Google ScholarPubMed
IntHout, J, Ioannidis, JPA and Borm, GF (2014) The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard Dersimonian-Laird method. BMC Medical Research Methodology 14, 25. https://doi.org/10.1186/1471-2288-14-25CrossRefGoogle ScholarPubMed
IntHout, J, et al. (2016) Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open 6, e010247. https://doi.org/10.1136/bmjopen-2015-010247CrossRefGoogle ScholarPubMed
Schünemann, H, et al. (2011) The grade approach and Bradford hill’s criteria for causation. Journal of Epidemiology and Community Health 65, 392. https://doi.org/10.1136/jech.2010.119933CrossRefGoogle ScholarPubMed
Al-Aly, Z, Bowe, B and Xie, Y (2022) Long covid after breakthrough Sars-Cov-2 infection. Nature Medicine 28, 14611467. https://doi.org/10.1038/s41591-022-01840-0CrossRefGoogle ScholarPubMed
Ayoubkhani, D, et al. (2022a) Risk of long covid in people infected with severe acute respiratory syndrome coronavirus 2 after 2 doses of a coronavirus disease 2019 vaccine: Community-based, matched cohort study. Open Forum Infectious Diseases 9, ofac464. https://doi.org/10.1093/ofid/ofac464CrossRefGoogle ScholarPubMed
Ballouz, T, et al. (2023) Post covid-19 condition after wildtype, delta, and omicron Sars-Cov-2 infection and prior vaccination: Pooled analysis of two population-based cohorts. PlosOne 18, e0281429. https://doi.org/10.1371/journal.pone.0281429CrossRefGoogle ScholarPubMed
Brannock, D, et al. (2023) Long covid risk and pre-covid vaccination in an EHR-based cohort study from the recover program. Nature Communications 14, 2914. https://doi.org/10.1038/s41467-023-38388-7CrossRefGoogle Scholar
Emecen, AN, et al. (2022) The presence of symptoms within 6 months after covid-19: A single-center longitudinal study. Irish Journal of Medical Science 192, 741750. https://doi.org/10.1007/s11845-022-03072-0CrossRefGoogle ScholarPubMed
Hastie, CE, et al. (2022) Outcomes among confirmed cases and a matched comparison group in the long-covid in Scotland study. Nature Communications 13, 5663. https://doi.org/10.1038/s41467-022-33415-5CrossRefGoogle Scholar
Ioannou, GN, et al. (2022) Rates and factors associated with documentation of diagnostic codes for long covid in the national veterans affairs health care system. JAMA Network Open 5, E2224359. https://doi.org/10.1001/jamanetworkopen.2022.24359CrossRefGoogle ScholarPubMed
Jassat, W, et al. (2023) A cohort study of post-covid-19 condition across the beta, delta, and omicron waves in South Africa: 6-month follow-up of hospitalized and nonhospitalized participants. International Journal of Infectious Diseases 128, 102111. https://doi.org/10.1016/j.ijid.2022.12.036CrossRefGoogle ScholarPubMed
Nascimento, TC, et al. (2023) Vaccination status and long covid symptoms in patients discharged from hospital. Scientific Reports 13, 2481. https://doi.org/10.1038/s41598-023-28839-yCrossRefGoogle ScholarPubMed
Simon, MA, Luginbuhl, R and Parker, R.(2021) Reduced incidence of long-covid symptoms related to administration of covid-19 vaccines both before covid-19 diagnosis and up to 12 weeks after. medRxiv. Epub November 17, 2021. https://doi.org/10.1101/2021.11.17.21263608CrossRefGoogle Scholar
Taquet, M, Dercon, Q and Harrison, PJ (2022) Six-month sequelae of post-vaccination Sars-Cov-2 infection: A retrospective cohort study of 10,024 breakthrough infections. Brain, Behavior, and Immunity 103, 154162. https://doi.org/10.1016/j.bbi.2022.04.013CrossRefGoogle Scholar
Public Health Agency of Canada Covid-19: Longer-term symptoms among Canadian Adults - Second Report. Ottawa, Canada: Public Health Agency of Canada, March 24, 2023. Report No. Available at https://health-infobase.canada.ca/covid-19/post-covid-condition/spring-2023-report.html (accessed 17 April 2023).Google Scholar
Spiliopoulos, L, et al. (2022) Post-acute symptoms four months after Sars-Cov-2 infection during the omicron period: A nationwide Danish questionnaire study. medRxiv. Epub October 12, 2022. https://doi.org/10.1101/2022.10.12.22280990CrossRefGoogle Scholar
Kahlert, CR, et al. (2023) Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 (Sars-Cov-2) infection by viral variant and vaccination status: A multicenter cross-sectional study. Clinical Infectious Diseases:ciad143. https://doi.org/10.1093/cid/ciad143CrossRefGoogle Scholar
Ayoubkhani, D, et al. (2022b) Trajectory of long covid symptoms after covid-19 vaccination: Community based cohort study. British Medical Journal 377, e069676. https://doi.org/10.1136/bmj-2021-069676CrossRefGoogle ScholarPubMed
Diez-Cirarda, M, et al. (2023) Multimodal neuroimaging in post-covid syndrome and correlation with cognition. Brain 146, 21422152. https://doi.org/10.1093/brain/awac384CrossRefGoogle ScholarPubMed
Arnold, DT, et al.(2021) Are vaccines safe in patients with long covid? A prospective observational study. medRxiv. Epub March 11, 2021. https://doi.org/10.1101/2021.03.11.21253225CrossRefGoogle Scholar
Tran, V-T, et al.(2023) Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with long covid: Target trial emulation based on compare e-cohort. BMJ Medicine 2, e000229. https://doi.org/10.1136/bmjmed-2022-000229CrossRefGoogle ScholarPubMed
Wynberg, E, et al. (2022) The effect of Sars-Cov-2 vaccination on post-acute sequelae of covid-19 (PASC): A prospective cohort study. Vaccine 40, 44244431. https://doi.org/10.1016/j.vaccine.2022.05.090CrossRefGoogle ScholarPubMed
Wisnivesky, JP, et al. (2022) Association of vaccination with the persistence of post-covid symptoms. Journal of General Internal Medicine 37, 17481753. https://doi.org/10.1007/s11606-022-07465-wCrossRefGoogle ScholarPubMed
Peghin, M, et al. (2022) Post-covid-19 syndrome and humoral response association after 1 year in vaccinated and unvaccinated patients. Clinical Microbiology and Infection 28, 11401148. https://doi.org/10.1016/j.cmi.2022.03.016CrossRefGoogle ScholarPubMed
Nehme, M, et al. (2022) Symptoms after covid-19 vaccination in patients with post-acute sequelae of Sars-Cov-2. Journal of General Internal Medicine 37, 15851588. https://doi.org/10.1007/s11606-022-07443-2CrossRefGoogle ScholarPubMed
Suyanto, S, et al. (2022) The quality of life of coronavirus disease survivors living in rural and urban area of Riau province, Indonesia. Infectious Disease Reports 14, 3342. https://doi.org/10.3390/idr14010005CrossRefGoogle Scholar
Strain, WD, et al. (2022) The impact of covid vaccination on symptoms of long covid: An international survey of people with lived experience of long covid. Vaccine 10, 652. https://doi.org/10.3390/vaccines10050652CrossRefGoogle ScholarPubMed
Krishna, B, et al.(2022) Spontaneous, persistent t-cell dependent ifn-γ release in patients who progress to long covid. Research Square. Epub November 21, 2022. https://doi.org/10.21203/rs.3.rs-2034285/v2CrossRefGoogle Scholar
Raw, RK, et al. (2021) Previous covid-19 infection, but not long-covid, is associated with increased adverse events following bnt162b2/pfizer vaccination. Journal of Infection 83, 381412. https://doi.org/10.1016/j.jinf.2021.05.035CrossRefGoogle Scholar
Gaber, TAZK, et al. (2021) Are mRNA covid 19 vaccines safe in long covid patients? A health care workers perspective. British Journal of Medical Practitioners 14, a008.Google Scholar
Bowe, B, Xie, Y and Al-Aly, Z (2022) Acute and postacute sequelae associated with Sars-Cov-2 reinfection. Nature Medicine; 28, 23982405. https://doi.org/10.1038/s41591-022-02051-3CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. PRISMA flow diagram of articles through the systematic review process.

Figure 1

Table 1. General characteristics of the 31 included primary research publications on post COVID-19 condition and vaccination, grouped by research questiona

Figure 2

Figure 2. Meta-analysis of the effect of vaccination prior to COVID-19 compared to unvaccinated on the odds of developing PCC, stratified by number of doses.

Figure 3

Figure 3. Meta-analysis of the hazard ratios for developing PCC in those vaccinated prior to COVID-19 compared to unvaccinated, stratified by number of doses.

Figure 4

Table 2. Summary of findings table for the main outcomes of PCC development or remission. Separated by odds ratios/hazard ratios, number of vaccine doses, and type of vaccine

Supplementary material: File

Jennings et al. supplementary material 1
Download undefined(File)
File 33 KB
Supplementary material: File

Jennings et al. supplementary material 2
Download undefined(File)
File 31 KB
Supplementary material: File

Jennings et al. supplementary material 3
Download undefined(File)
File 34 KB
Supplementary material: File

Jennings et al. supplementary material 4
Download undefined(File)
File 22 KB
Supplementary material: File

Jennings et al. supplementary material 5
Download undefined(File)
File 29 KB
Supplementary material: File

Jennings et al. supplementary material 6
Download undefined(File)
File 21 KB