Table 1.

Studies investigating SARS-CoV-2 vaccination for the prevention of long COVID (n = 9).

Study	Country	Study Design	Sample Source	Total Sample	Vaccinated (Treatment) Group	Control Group	Long COVID Definition/Persistent COVID-19 Symptoms and Frequency	Summary of Findings
Al-Aly et al., 2021*	United States	Retrospective Cohort	United States Veterans Health Administration (VHA) EHR	n = 64 571 Age range: ≥18 Mean (SD) age*: 66.62 (13.79) Mean (SD) age**: 56.07 (15.72) Sex (%F/%M)*: 8.68/91.32 Sex (%F/%M)**: 14.15/85.85 *breakthrough cases, prior to weighting **no prior SARS-CoV-2 vaccination, prior to weighting	•n = 16 035 received Janssen Ad26.COV2.S, Moderna mRNA-1273, or Pfizer-BioNTech BNT162b2 vaccination prior to first positive COVID-19 test (breakthrough cases, treatment group)	•n = 48 536 without prior COVID-19 vaccination, with COVID-19 positive test, and alive 30 days after date of first positive COVID-19 test (control group) •Treatment and control groups were weighted for analysis	•6 month burden of post-acute sequelae (cardiovascular, coagulation, gastrointestinal, kidney, mental health, metabolic, musculoskeletal, neurologic, and the pulmonary system, as well as fatigue) •Outcomes assessed starting from 30 days after date of first positive COVID-19 test •Incident post-acute sequelae examined in cohort with no record of the condition in the year prior to date of first positive COVID-19 test	Those with breakthrough COVID-19 exhibited a lower risk of post-acute sequelae and burden (-30.60; 95% CI −42.25, −18.49) compared to those with COVID-19 and no prior history of SARS-CoV-2 vaccination. The risk of post-acute sequelae in the cardiovascular, coagulation, metabolic, and pulmonary organ systems, as well as risk of fatigue, was lower in those with breakthrough COVID-19 vs. those with COVID-19 and without prior SARS-CoV-2 vaccination. The lower risk was not statistically significant for post-acute sequelae in affecting the kidney, gastrointestinal, mental health, and neurologic organ systems.
Antonelli et al., 2022	United Kingdom	Case-control	COVID Symptom Study mobile phone app	n = 16,800 Age range: ≥18 Mean (SD) age*: 50.2 (14.1) Mean (SD) age**: 52.9 (13.5) Mean (SD) age***: 51.7 (14.5) Mean (SD) age****: 54.0 (13.1) Sex (%F/%M)*: 62.5/37.5 Sex (%F/%M)**: 61.2/38.8 Sex (%F/%M)***: 62.5/37.5 Sex (%F/%M)****: 61.2/38.8 *cases 1 **cases 2 ***controls 1 ****controls 2	•Received a first or second dose of a SARS-CoV-2 vaccine (Pfizer-BioNTech BNT162b2, Oxford- AstraZeneca ChAdOx1 nCoV-19, or Moderna mRNA-1273) •Had either a positive COVID-19 test (RT-PCR or lateral flow) at least 14 days after their first vaccination but before their second (n = 6030; cases 1), or a positive test at least 7 days after their second vaccination (n = 2370; cases 2) •≥14 days of app use after testing positive for COVID-19 (n = 3825 cases 3, and n = 906 cases 4, subsets of cases 1 and 2, respectively)	•Negative COVID-19 test at least 14 days after first COVID-19 vaccination but before second (n = 6030; controls 1), or reporting a negative COVID-19 test at least 7 days after second vaccination (n = 2370; controls 2) •No prior SARS-CoV-2 vaccination, reporting a positive COVID-19 test, and ≥ 14 days of app use after testing positive (n = 3825; controls 3, and n = 906; controls 4, matched to cases 3 and 4, respectively)	•Self-reported via COVID Symptom Study mobile phone app •Symptoms lasting ≥28 days after post-vaccination infection	The odds of reporting persistent symptoms were approximately halved (OR 0.51, 95% CI 0.32–0.82, p = 0.0015) by having two SARS-CoV-2 vaccine doses. The odds of reporting persistent symptoms were not significantly associated with one prior SARS-CoV-2 vaccine dose (OR 1.04, 95% CI 0.86–1.25, p = 0.691). Reported rates of persistent symptoms lasting ≥ 28 days post-infection are as follows: cases 3: 229/2479 (9.2%) cases 4: 31/592 (5.2%) controls 3: 296/2762 (10.7%) controls 4: 55/482 (4%)
Arjun et al., 2022*	India	Retrospective Cohort	Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences Bhubaneswar	n = 487 Age range: ≥18 Mean (SD) age: 39 (15) Sex (%F/%M): 40.9/59.1	•RT-PCR confirmed SARS-COV-2 infection and either hospitalized or treated as outpatients •n = 287 (58.9%) received two doses of a SARS-CoV-2 vaccine, n = 81 (16.6%) received one dose •Majority vaccinated with Serum Institute of India Covovax	•n = 119 (24.5%) did not receive a SARS-CoV-2 vaccine	•As per NICE guidelines, individuals were contacted via telephone >4 weeks from date of COVID-19 diagnosis •Self-report of long COVID symptoms •Median follow-up of 44 days (IQR 39–47) •Long COVID was reported by 29.2% (95% CI: 25.3–33.4%) of participants	Having received 2 doses of SARS-CoV-2 vaccination was significantly associated with long COVID (aOR 2.32, 95% CI 1.17–4.58, p = 0.01). One dose was not significantly associated with long COVID.
Herman et al., 2022*	Indonesia	Retrospective cohort	Indonesian POST-COVID retrospective longitudinal data (online questionnaire)	n = 442 Mean (SD) age*: 31.60 (8.58) Mean (SD) age**: 32.49 (10.39) (%F/%M)*: 50.2/49.8 Sex (%F/%M)**: 49.8/50.2 *double vaccinated, after matching **unvaccinated, after matching	•n = 221 fully vaccinated (i.e. 2 doses) and infected with SARS-CoV-2>14 days following full vaccination (confirmed by RT-PCR and/or Antigen test). •The majority received 2 doses of the inactivated viral vaccine (n = 441 Sinovac, n = 1 Oxford-AstraZeneca). •The average period to reach full vaccination with the inactivated viral vaccine was 24±6.41 days; during this time, no heterologous vaccine, and booster were administered	•n = 221 infected with SARS-CoV-2<14 days following full SARS-CoV-2 vaccination or not fully vaccinated for SARS-CoV-2 (either incomplete or unvaccinated) •1:1 propensity-score matched individuals unvaccinated or vaccinated with 1 dose for COVID-19 or infected <14 days of full vaccination	•Long COVID defined as ‘signs and symptoms developed during or following a disease consistent with COVID-19 and which continue for >4 weeks but are not explained by alternative diagnosis.” •Olfactory dysfunction was assessed at 2 and 4 weeks after negative conversion via PCR using a self-measured mini olfactory questionnaire (MOQ)	Breakthrough infections occurring > 14 days following full SARS-CoV-2 vaccination were associated with a 69% lower odds of developing olfactory dysfunction (aOR 0.31, 95% CI 0.102–0.941). The greater the interval between the second dose and SARS-CoV-2 infection, the greater the odds of developing long COVID (aOR 1.012 95% CI 1.002–1.022, p = 0.015).
Kuodi et al., 2022*	Israel	Cross-sectional (nested in prospective cohort)	Ziv Medical Centre, Padeh-Poriya Medical Centre, and Galilee Medical Centre	n = 3388 Age range: >18 Mean age: N/A Sex (%F/%M): N/A	•n = 340 (36%) vaccinated with 1 dose of Pfizer-BioNTech BNT162b2 and RT-PCR tested positive for COVID-19 •n = 294 (31%) vaccinated with 2 + doses of Pfizer-BioNTech BNT162b2 and RT-PCR tested positive for COVID-19 •Some individuals were infected prior to vaccination while others were breakthrough cases •Because of vaccination policy in Israel at the time that recommended a single dose for previously infected individuals, it is likely that most individuals who received a single dose were infected prior to vaccination whereas those who received two doses were infected after receiving their vaccines	•n = 317 unvaccinated for SARS-CoV-2 and RT-PCR tested positive for COVID-19 (control 1) •n = 2437 unvaccinated for SARS-CoV-2 and RT-PCR tested negative for COVID-19 (control 2)	•Assessed via modified ISARIC online questionnaire •337/951 (35%) of infected participants reported not fully recovering from initial COVID-19 symptoms at follow-up •The most commonly reported persistent symptoms were fatigue (22%), headache (20%), weakness in arms or legs (13%), and persistent muscle pain (10%) •The median (IQR) time between acute illness and reporting symptoms 302 (2 9 6) days	After adjusting for follow-up time and baseline symptoms, those who received two SARS-CoV-2 vaccine doses were less likely than unvaccinated individuals to report post-COVID fatigue by 64%, headache by 54%, arm or leg weakness by 57%, and muscle pain by 68% (RRs 0.36, 0.46, 0.43, 0.32; p < 0.04 in the listed sequence). Those who received two SARS-CoV-2 vaccine doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection. Adjusted RR for recovery from COVID-19 following two doses 0.981 (0.798–1.206, p = 0.856). The foregoing associations were largely not seen amongst individuals who received a single dose of a SARS-CoV-2 vaccine, who were in most cases likely to have been infected prior to vaccination within this study (recovery from COVID-19 unadjusted RR 1.019, 95% CI 0.893–1.163, p = 0.778).
Senjam et al., 2021*	India	Cross-sectional	Tertiary healthcare institute in Delhi	n = 773 Age range: >18 Median age: 34 (IQR 27–44) Sex (%F/%M): 43.6/56.4	•n = 191 (24.7%) received two doses prior to testing positive for SARS-CoV-2 (RT-PCR or CB-NAAT test self-reported by study participants) •n = 175 (22.6%) received one dose prior to testing positive for SARS-CoV	•n = 407 (52.7%) unvaccinated when infected with SARS-CoV-2	•Symptom(s) persisting >4 weeks from date of SARS-CoV-2 positive test •Assessed via proprietary semi-structured questionnaire (administered online remotely) •n = 257 (33.2%) reported short term post COVID-19 symptoms (ST-PCS): symptoms present >4 weeks after the SARS-CoV-2 positive test and lasting ≤ 12 weeks •n = 99 (12.8%) reported long term post COVID-19 symptoms (LT-PCS): symptoms present >12 weeks after SARS-CoV-2 positive test •The most prevalent symptoms were fatigue (79.3%), pain in the joints (33.4%),and muscle (29.9%), hair loss (28.0%), headache (27.2%), breathlessness (25.3%), sleep disturbance (25.3%), and cough (24.9%)	Receiving two doses of a SARS-CoV-2 vaccine prior to infection was associated with a reduction in the odds of self-reported long COVID (aOR 0.55; 95 %CI 0.37–0.85). One dose was not associated with a protective effect against the development of long COVID (aOR 1.00, 95% CI 0.66–1.49).
Simon et al., 2021**	United States	Retrospective Cohort	Arcadia Data Research	n = 240 648 Age range: N/A Mean (SD) age: N/A Sex (%F/%M): 59.9/40.1	•n = 2 392 (1.0%) individuals received their first COVID-19 vaccination prior (mRNA vaccines [Pfizer-BioNTech and Moderna] or the inactivated viral vaccine [Janssen]) to COVID-19 diagnosis (ICD-10 code U07.1 at any time or B97.29 prior to May 2020 in a medical encounter, or received a positive result from a COVID-19 nucleic acid amplification or antigen test result)	•n = 220 460 (91.6%) had not received any vaccine against COVID-19 prior to COVID-19 diagnosis or up to 12-weeks after their COVID-19 diagnosis (reference group)	•Distinct long COVID symptoms reported 12 + weeks following COVID-19 diagnosis, categorized by body system (cardiovascular, constitutional, ears/nose/mouth/throat, gastrointestinal, musculoskeletal, neurological, and/or respiratory) •n = 90 319 (37.5%) reported any long COVID symptoms, n = 40 578 (16.9%) reported 2 + symptoms	Individuals who received one dose of a SARS-CoV-2 vaccine prior to COVID-19 infection were 4.5x less likely to report any long COVID symptom (OR 0.220, 95% CI 0.196–0.245, p < 0.005) and 8.8x less likely to report 2 + long COVID symptoms. The foregoing result applies regardless of the manufacturer of the vaccine.
Taquet et al., 2021*	United States	Retrospective Cohort	TriNetX EHR network	n = 18 958 Age range: N/A Mean (SD) age*: 56.5 (18.0) Mean (SD) age**: 57.6 (20.6) Sex (%F/%M)*:59.9/40.1 Sex (%F/%M)**:60.8/39.2 71.6% white* 72.5% white** *vaccinated (matched) **unvaccinated (matched)	•n = 9479 individuals received a SARS-CoV-2 vaccine (BNT162b2 Pfizer-BioNTech, mRNA-1273 Moderna, or Ad26.COV2.S Janssen) at least 2 weeks prior to COVID-19 infection (ICD-10 code U07.1 or positive PCR)	•1:1 propensity-score matched individuals unvaccinated for COVID-19 who had received an influenza vaccine at any time	•ICD-10 codes representing documented COVID-19 sequelae occurring in the 6 months after a confirmed COVID-19 infection •long COVID features include any of the following: abdominal symptoms, abnormal breathing, anxiety/depression, chest/throat pain, cognitive symptoms, fatigue, headache, myalgia, other pain	Receiving at least one SARS-CoV-2 vaccine dose prior to infection was not significantly associated with decreased of reporting any long COVID features (HR 1.01, 95% CI 0.96–1.05, p = 0.83, Bonferroni-corrected p = 1.0), The risk of several individual long COVID features were negatively associated with prior SARS-CoV-2 vaccination, but did not survive correction for multiple comparisons: myalgia (HR 0.78, 332 95% CI 0.67–0.91), fatigue (HR 0.89, 95% CI 0.81–0.97), and pain (HR 0.90, 95% CI 0.81–0.99), with potentially additional protection after a second dose of the SARS-CoV-2 vaccine against abnormal breathing (HR 0.89, 95% CI 0.81–0.98) and cognitive symptoms (HR 0.87, 95% CI 0.76–0.99).
Office of National Statistics Data Ayoubkhani et al., 2022	United Kingdom	Prospective Cohort	UK Coronavirus (COVID-19) Infection Survey [CIS]) data to November 2021	n = 6 180 Age range: 18–69 Mean (SD) age*: 49.0 (12.0) Mean (SD) age**: 46.7 (11.2) Sex (%F/%M)*: 54.2/45.8 Sex (%F/%M)**: 53.7/46.3 91.8% white* 91.2% white** *double vaccinated, after matching **unvaccinated, after matching	•n = 3090 received two doses of a SARS-CoV-2 vaccine (Oxford/AstraZeneca ChAdOx1 nCoV-19, Pfizer/BioNTech BNT162b2, and/or Moderna mRNA-1273) at least two weeks prior to testing positive for COVID-19 (PCR at study visits, or any swab test in national testing programmes as self-reported by study participants)	•n = 3090 individuals unvaccinated when infected, and remained so at their first follow-up visit at least 12 weeks later •Double-vaccinated and unvaccinated participants were 1:1 propensity-score matched	•Symptoms self-reported at least 12 weeks after COVID-19 infection	Receiving two doses of a SARS-COV-2 vaccine prior to infection was associated with a 41.1% decrease in the odds of self-reported long COVID, relative to socio-demographically similar study participants who were not vaccinated when infected (aOR 0.589, 95% CI 0.501–0.691). 9.5% (95% CI 8.5–10.6%) of double vaccinated individuals reported long COVID symptoms of any severity vs.14.6% (95% CI 13.4–15.9%) unvaccinated individuals. The corresponding estimates for long COVID symptoms severe enough to result in limitation to day-to-day activities were 5.5% (95% CI 4.8–6.4%) and 8.7% (95% CI 7.7–9.7%), respectively. There was no statistically significant difference in outcomes between adenovirus vector (aOR 0.623, 95% CI 0.514–0.714) vs. mRNA (aOR 0.504, 95% CI 0.370–0.685) vaccines.

*preprint article (not peer-reviewed) as of January 28, 2022.

**Simon et al. reported on both vaccination prior to development of long COVID, and vaccination post factum.

Age is reported in years. ‘Doses’ refer to SARS-CoV-2 vaccine doses.

Acronyms: N/A: Not Available, SF-36: Short Form-36 Health Survey, WEMWBS: Warwick–Edinburgh Mental Wellbeing Scale, 95% CI: 95% confidence interval, OR: odds ratio, aOR: adjusted OR, HR: hazard ratio, RR: relative risk, COVID-19: coronavirus 2019.