key: cord-0278514-qh6fqna8
authors: Kuodi, P.; Gorelik, Y.; Zayyad, H.; Wertheim, O.; Beiruti Wiegler, K.; Abu Jabal, K.; Dror, A.; Nazzal, S.; Glikman, D.; Edelstein, M.
title: Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients infected between March 2020 and November 2021
date: 2022-01-06
journal: nan
DOI: 10.1101/2022.01.05.22268800
sha: 8641eb332eed76cffc0696b939acd06378df2264
doc_id: 278514
cord_uid: qh6fqna8

Background: Long COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID19 is not well understood. We determined whether vaccination was associated with reporting long-term symptoms post-SARS-CoV-2 infection by comparing, among individuals previously infected with SARS-CoV-2, those who were vaccinated to those who were not, in terms of self-reported long-term symptoms. Methods: We invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-June 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated in terms of self-reported symptoms post-acute infection. Results: Of 951 previously infected individuals who filled the survey 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, fully vaccinated (2 or more doses) individuals were less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Conclusions: Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID19 symptoms. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.

Long coronavirus disease 2019 (Long COVID), also known as post-COVID-19 syndrome, is an emerging and complex health problem that remains poorly characterised. In October 2021, the World Health Organization (WHO) defined long COVID as "A condition which occurs in individuals with a history of probable or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, usually three months from the onset of COVID-19 with symptoms that last for at least two months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction but also others involving the musculo-skeletal, cardiac and central nervous systems, which generally have an impact on everyday functioning" [1] . Symptoms of long COVID may fluctuate or relapse over time. Patients purported to have long COVID have reported a wide range of symptoms but the most prevalent symptoms include;

fatigue (approximately 58%), shortness of breath (24%), joint pain (19%), chest pain (16%) [2, 3] , headache (44%), palpitations (11%), physical limitations, depression (12%) and insomnia (11%) [3, 4] . These symptoms may emerge after the initial recovery from an acute COVID-19 episode, or be persistent symptoms that do not resolve following the initial COVID-19 illness [5] .

Vaccination against SARS-CoV-2 infection is one of the most important interventions deployed to mitigate the COVID-19 pandemic. As of October 2021, the WHO has listed the Pfizer/BioNTech, AstraZeneca-SK Bio, Sinopharm, Serum Institute of India, Janssen, and Moderna vaccines for emergency use under the Emergency Use Authorisation (EUA) [6] . In August 2021, the Food and Drugs Administration (FDA) approved the Pfizer/BioNTech vaccine as the first vaccine for use to prevent COVID-19 in individuals sixteen years and older [7] .

The first COVID-19 vaccine campaign with a WHO-approved vaccine started in December 2020, following the authorisation of the Pfizer/BioNTech mRNA vaccine by the FDA for emergency use. By January 2022, over 58% of the world population had received at least one dose of the EUA COVID-19 vaccines, accounting for 9.2 billion COVID-19 doses [8] . Available evidence demonstrates that COVID19

vaccines are effective in preventing severe complications of COVID-19 and death [9] , including in cases of infection with the Delta and Omicron variants of SARS-CoV-2 [10] [11] [12] , variants that are more contagious than the ancestral SARS-CoV-2 variants [12, 13] . In Israel, the COVID-19 vaccination campaign started in December 2020, and by January 2022, approximately 63.6% of the entire population had received a priming, two-dose course, mainly with the BNT162b2 mRNA vaccine [14] and 45.6%

had received a third dose of COVID-19 vaccines, available in Israel from June 2021.

The third dose demonstrated high effectiveness against severe outcomes in the context of waning immunity six months post-priming course [14] . During the study period, individuals previously infected with SARS-CoV-2 were eligible for a single dose of the BNT162b2 mRNA vaccine. All other individuals with no history of SARS-CoV-2 infection were eligible for a first and a second dose with eligibility for the second dose at three weeks from the date of the first dose.

Risk factors for developing long COVID have not been fully explored. So far,

increasing age, pre-existing health conditions such as hypertension, obesity, psychiatric disorders, and immunosuppression have been associated with an increased risk of long COVID [15] . As the process to establish a more specific case definition of long COVID continues, little is known about the impact of COVID-19 vaccination on long COVID. A large prospective study reported an association between vaccination and lower self-reporting of symptoms beyond 28 days among SARS-CoV-2 infected individuals without reporting details on specific symptoms or duration [16] . Findings from one study (in preprint) suggests vaccination reduces the reporting of some, but not all post-acute COVID-19 sequelae 6 months post-infection individuals previously infected with SARS-CoV-2, those who were vaccinated to those who were not in terms of self-reported long-term symptoms.

The current study reports results of a cross-sectional study nested in a prospective longitudinal cohort study to assess risk of and risk factors for long-term physical, mental, and psychosocial consequences of COVID-19. The ISARIC questionnaire was adapted to the Israeli context. Study participants were asked to select from a list all symptoms they were currently experiencing.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The online survey included information about socio-demographic status (place of residence, age, sex, ethnicity/religious affiliation, education level and income), baseline health status: (Body mass index [BMI] and chronic conditions), information related to the clinical experience and symptoms experienced during the initial COVID-19 diagnosis, SARS-CoV-2 test results, vaccination status, number of doses, type of vaccine and date of administration. Participants were also asked to report symptoms experienced at the time of filling the questionnaire. A simplified paper version of the questionnaire can be found in Appendix 1.

The primary outcome in this study was the proportion, overall, and in specific age groups, of previously infected participants reporting selected health outcomes among the vaccinated compared to the unvaccinated individuals. Vaccinated individuals were infected either before or after vaccination. The complete list of symptoms can be found in Table 1 .

We compared the vaccinated and unvaccinated groups' socio-demographic and health characteristics using Chi-square tests (for proportions) and Student's t-tests (for means). We also compared symptoms at presentation using Chi-square tests.

Proportions of long-term symptoms and selected health outcomes were calculated for each group with the total number of participants in each group taken as the denominator. We also compared the time elapsed between the onset of COVID-19 symptoms for symptomatic patients and the date of response to the survey in the two groups (vaccinated and unvaccinated) to establish whether they had comparable durations of follow-up.

A series of binary regression models were fitted to the data for the ten most commonly reported post-COVID-19 symptoms according to vaccination status. We adjusted for the difference in follow-up time and proportion of asymptomatic patients at the time of diagnosis between the groups. In addition, to take the anticipated age differences into account, the analysis was age-stratified and differences in the length . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 6, 2022. ; of time from the beginning of symptoms to responding to the survey were adjusted for in the model. Vaccination status was recorded as either unvaccinated, partial (one dose) or complete (two or more doses). Datasets were processed using Microsoft Excel and analysed using STATA version 15.

The study received ethical approvals from the Ziv Medical Centre, Padeh-Poriya Medical Centre, and Galilee Medical Centre ethical committees, reference numbers; 0007-21-ZIV, 009-21-POR, and 0018-21-NHR, respectively.

No specific funding was received for this study

Of 30,262 invitations to participate in the study, 2346 (7.8%) individuals responded to the survey and agreed to participate. Of these, 951 individuals reported testing positive for SARS-CoV-2 by PCR and were therefore included in the study. Table 1 ). Additionally, the reported symptoms were less frequent at the time of SARS-CoV-2 PCR testing among the fully vaccinated compared to the partially vaccinated and the unvaccinated ( Figure 1A ).

Compared with fully and partially vaccinated individuals, unvaccinated participants were younger (52 and 44 vs. 39 years, respectively, p<0.001, Table 1 ), reflecting the COVID-19 vaccination patterns in the general population. Consequently, pre-existing chronic conditions were more frequently reported in the vaccinated group (p<0.05).

The vaccinated and unvaccinated groups were comparable in terms of gender . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 6, 2022. ; distribution and socio-economic characteristics ( Table 1 ). The median time between acute illness and reporting symptoms was longer in the unvaccinated group compared to the fully vaccinated (8 vs. 4 months, p<0.05). Out of 951 participants, 85 (9%) reported having been hospitalized with comparable proportions in the fully vaccinated, partially vaccinated and the unvaccinated (p=0.27, Table 1 ).

Of the 951 participants, 337 (35%) reported not fully recovering from the initial COVID-19 symptoms at follow-up. The most commonly reported symptoms at the time of follow-up were fatigue (22%), headache (20%), and weakness in arms or legs (13%) (Table 2, Figure 1B ).

Compared with unvaccinated participants, those fully vaccinated were 36-73% less likely to report eight of the ten most commonly reported symptoms (p<0.04 for all, Table 3 ). After adjusting for duration of follow-up and presence of symptoms at baseline, a 54-82% reduction in reporting symptoms among those fully vaccinated for seven of the ten most commonly reported symptoms was detected (Table 3 ). In the unadjusted age-stratified analysis, differences in reported symptoms were primarily seen in the older age groups, in particular those aged above 60 years who were also 68% more likely to report feeling fully recovered compared with their unvaccinated peers of the same age (Table 3 , p<0.004). Although the risk ratio remained high in the adjusted analysis (RR 1.7), the result was no longer significant, likely due to loss of statistical power.

Overall, full vaccination (2 or more vaccines) was associated with a substantial decrease in reporting the most common post-COVID-19 symptoms, and an increase in reporting full recovery, specifically in individuals aged above 60 years. These associations were largely not seen among individuals who received a single dose of a COVID-19 vaccine. The results are consistent with the few other available studies . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. showed that the associations reported in the current study were largely confined to older age groups (above 60 years), a finding not consistent with a previous study reporting that the protective effect was confined to younger age groups [17]. Our analysis does not allow us to establish why the beneficial effect of the COVID-19 vaccine on long-term symptoms seems to be stronger in older age groups. A plausible explanation for the association found in the older individuals could be that younger individuals have more physiological reserve and are therefore able to recover on their own, which is not the case in older adults. Other studies have reported that frailty was associated with both age and worse outcomes following

The unvaccinated and the vaccinated groups were comparable in sociodemographic characteristics except for age, reflecting vaccine coverage in the Israeli population [24] . As a result, some chronic conditions present at baseline were more common in the vaccinated group. However, since these conditions are more common in the older fully vaccinated group, we would anticipate even bigger differences between the vaccinated and unvaccinated group had we taken them into account in the analysis. This difference in age between the vaccinated and the unvaccinated individuals is consistent with the COVID-19 vaccination strategy implemented by the Israeli Ministry of Health, which targeted the older population during the initial stages of the COVID-19 vaccination rollout. The vaccinated and unvaccinated populations differed in terms of distribution of symptoms and proportion of asymptomatic individuals at acute COVID-19 presentation. A higher proportion of fully vaccinated group were asymptomatic at the time of diagnosis compared to the unvaccinated group, and those who were symptomatic at baseline reported less symptoms compared with those unvaccinated. These figures reflect the protection against symptomatic disease conferred by vaccines, which may also partly explain the lower proportion of reporting long-term symptoms among those vaccinated. However, the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. ; protective effect of vaccination against long term symptoms persisted after adjusting for asymptomatic disease, suggesting a reduction in reported long COVID symptoms even among those symptomatic at the time of infection. The median follow-up duration was longer in the unvaccinated group than the vaccinated individuals. One could therefore expect less symptoms in the unvaccinated as a result of having a longer time period to recover; however, the opposite was observed, and in any case the protective effect of vaccination remained after adjusting for follow up time. The adjusted model suggested an even stronger protective effect of vaccination against reported long-term symptoms. However, we believe that the study was underpowered to detect age specific differences using an adjusted regression model.

Our study relied on self reported positive PCR results. In Israel, most individuals have been PCR-tested multiple times for a range of reasons including being symptomatic, travelling, contact tracing, and screening. Specimens for the same patients are tested in different laboratories. Therefore, using positive lab results from a selection of laboratories (rather than all laboratories in the country) could lead to misclassification. Considering the consequences on daily life, including quarantine, It is unlikely that someone would forget having tested positive for SARS-CoV-2, or vice versa. It is also important to note that the vaccination policy in Israel, at the time of the survey, specified that SARS-CoV-2-infected individuals were in theory only eligible for a single dose of vaccine. Therefore, individuals who were partially vaccinated also differed from those fully vaccinated in terms of the sequence of events: while those who received two doses will have mostly been infected after having been fully vaccinated, many among those who received a single dose will have been infected prior to vaccination. Although our data does not allow to establish this sequence of events for each individual, the follow up time and symptoms at presentation reflect this difference. Infection prior to vaccination could partially explain the observed lack of effect of one dose of vaccine regarding long-term reported symptoms. The effect of vaccination on long-term sequelae according to the infection/vaccination sequence warrants further research. With few patients reporting having been hospitalised, our cohort reflects the mild end of the COVID-19 spectrum, and the results cannot necessarily be extrapolated to patients who were more severely ill (and hospitalised) in the acute phase of the illness. Our study did not include children who are less likely to develop severe acute illness following . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268800 doi: medRxiv preprint 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. ; .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 6, 2022. Significantly less frequent among the fully vaccinated compared to the unvaccinated or the partially vaccinated . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268800 doi: medRxiv preprint CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 6, 2022. ;

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