# Vaccine Effectiveness against Symptomatic SARS-CoV-2 Infection in Adults Aged 65 Years and Older in Primary Care: I-MOVE-COVID-19 Project, Europe, December 2020 to May 2021

Esther Kissling, Mariëtte Hooiveld, Virginia Sandonis Martin, Iván Martinez-Baz, Naoma William, Ana-Maria Vilcu, Clara Mazagatos, Lisa Domegan, Simon De Lusignan, Adam Meijer, et al.

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Esther Kissling, Mariëtte Hooiveld, Virginia Sandonis Martin, Iván Martinez-Baz, Naoma William, et al.. Vaccine Effectiveness against Symptomatic SARS-CoV-2 Infection in Adults Aged 65 Years and Older in Primary Care: I-MOVE-COVID-19 Project, Europe, December 2020 to May 2021. Eurosurveillance, 2021, 26 (29), 10.2807/1560-7917.ES.2021.26.29.2100670. hal-03846535

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Distributed under a Creative Commons Attribution 4.0 International License
Vaccine effectiveness against symptomatic SARS-CoV-2
infection in adults aged 65 years and older in primary
care: I-MOVE-COVID-19 project, Europe, December
2020 to May 2021

Esther Kissling¹, Mariette Hooiveld², Virginia Sandonis Martín³, Iván Martínez-Baz⁴,⁵, Naoma William⁶, Ana-Maria Vilcu⁷, Clara Mazagatos⁵,⁸, Lisa Domegan⁹, Simon de Lusignan¹⁰,¹¹, Adam Meijer¹², Ausenda Machado¹³, Mia Brytting¹⁴, Itziar Casado⁴,⁵, Josephine-L K. Murray⁶, Sylvie Belhilli¹⁵,¹⁶, Amparo Larrauri⁵,⁸, Joan O'Donnell⁹, Ruby Tsang¹⁰,¹¹, Marit de Lange¹², Ana Paula Rodrigues¹³, Maximilian Riess¹⁴, Jesús Castilla⁴,⁵, Mark Hamilton⁶, Alessandra Falchi¹⁷, Francisco Pozo³, Linda Dunford¹⁸, Jade Cogdale¹⁹, Tessa Jansen², Raquel Guiomar¹³, Theresa Enkirch¹⁴, Cristina Burgui⁴,⁵, Debbie Sigerson⁶, Thierry Blanchon⁷, Eva María Martínez Ochoa²⁰, Jeff Connell¹⁸, Joanna Ellis¹⁹, Rianne van Gageldonk-Lafeber¹², Irina Kislaya¹³, Angela MC Rose¹, Marta Valenciano¹, I-MOVE-COVID-19 primary care study team²¹

1. Epiconcept, Paris, France

2. Nivel, Utrecht, the Netherlands

3. National Centre for Microbiology, Institute of Health Carlos III, Madrid, Spain

4. Instituto de Salud Pública de Navarra (IdiSNA), Pamplona, Spain

5. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Institute of Health Carlos III, Madrid, Spain

6. Public Health Scotland, Glasgow, Scotland

7. INSERM, Sorbonne Université, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France

8. National Centre for Epidemiology, Institute of Health Carlos III, Madrid, Spain

9. Health Service Executive-Health Protection Surveillance Centre, Dublin, Ireland

10. Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

11. Royal College of General Practitioners Research and Surveillance Centre, London, UK

12. National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands

13. Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

14. The Public Health Agency of Sweden, Stockholm, Sweden

15. Unité de Génétique Moléculaire des Virus à ARN, UMR 3569 CNRS, Université Paris Diderot SPC, Institut Pasteur, Paris, France

16. CNR des virus des infections respiratoires, Institut Pasteur, Paris, France

17. Laboratoire de Virologie, Université de Corse-Inserm, Corte, France

18. National Virus Reference Laboratory, University College Dublin, Dublin, Ireland

19. Public Health England, London, England

20. Servicio de Epidemiología y Prevención Sanitaria, Dirección General de Salud Pública, Consumo y Cuidados, La Rioja, Spain

21. The members of the I-MOVE-COVID-19 primary care study team are listed in the Investigators tab

Correspondence: Esther Kissling (e.kissling@epiconcept.fr)

Citation style for this article:

Kissling Esther, Hooiveld Mariette, Sandonis Martín Virginia, Martínez-Baz Iván, William Naoma, Vilcu Ana-Maria, Mazagatos Clara, Domegan Lisa, de Lusignan Simon, Meijer Adam, Machado Ausenda, Brytting Mia, Casado Itziar, Murray Josephine-L K., Belhilli Sylvie, Larrauri Amparo, O'Donnell Joan, Tsang Ruby, de Lange Marit, Rodrigues Ana Paula, Riess Maximilian, Castilla Jesús, Hamilton Mark, Falchi Alessandra, Pozo Francisco, Dunford Linda, Cogdale Jade, Jansen Tessa, Guiomar Raquel, Enkirch Theresa, Burgui Cristina, Sigerson Debbie, Blanchon Thierry, Martínez Ochoa Eva María, Connell Jeff, Ellis Joanna, van Gageldonk-Lafeber Rianne, Kislaya Irina, Rose Angela MC, Valenciano Marta, I-MOVE-COVID-19 primary care study team. Vaccine effectiveness against symptomatic SARS-CoV-2 infection in adults aged 65 years and older in primary care: I-MOVE-COVID-19 project, Europe, December 2020 to May 2021. Euro Surveill. 2021;26(29):pii=2100670. https://doi.org/10.2807/1560-7917.ES.2021.26.29.2100670

Article submitted on 05 Jul 2021 / accepted on 22 Jul 2021 / published on 22 Jul 2021

We measured COVID-19 vaccine effectiveness (VE)
against symptomatic SARS-CoV-2 infection at primary
care/outpatient level among adults ≥ 65 years old using
a multicentre test-negative design in eight European
countries. We included 592 SARS-CoV-2 cases and
4,372 test-negative controls in the main analysis. The
VE was 62% (95% CI: 45–74) for one dose only and
89% (95% CI: 79–94) for complete vaccination. COVID-
19 vaccines provide good protection against COVID-19
presentation at primary care/outpatient level, particu-
larly among fully vaccinated individuals.

The I-MOVE-COVID-19 network collates epidemio-
logical and clinical information on patients with coro-
navirus disease (COVID-19), including severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) viro-
logical characterisation in 11 European countries [1].

One component of I-MOVE-COVID-19 is the multicen-
tre vaccine effectiveness (VE) study at primary care/
outpatient level in nine European study sites in eight
countries. We measured overall and product-specific
COVID-19 VE against symptomatic SARS-CoV-2 infec-
tion among those aged 65 years and older. We also
measured VE by time since vaccination.

Participating study sites

The I-MOVE-COVID-19 primary care/outpatient study sites are: England, France, Ireland, the Netherlands, Portugal, Scotland, Spain (three regions), Spain (Navarra region) and Sweden (Table 1). Study sites adapted the I-MOVE-COVID-19 VE study protocol [2], to their country-specific setting. Sites included all, or a systematic sample of, acute respiratory infection (ARI) patients or patients presenting with common COVID-19

<figure><img src="image_2.png" /></figure>
symptoms (at least one of the following symptoms: fever, cough, shortness of breath, sudden onset of anosmia/ageusia) who contacted the sentinel physician (Table 1). The Navarra region included all patients presenting to the health service primary care physicians. A systematic sample of patients in COVID-19 testing centres both with and without physician referral were included in Portugal. Scotland included a systematic sample of patients presenting to community-based COVID-19 centres with self- and clinical staff-based swabbing.

Demographic and clinical information including age, sex, any underlying chronic conditions and conditions relevant to COVID-19 (diabetes, heart disease, chronic lung disease, immunodeficiencies), and COVID-19 vaccination status was collected (Table 1).

## Definitions of cases and controls and vaccination

We used the test-negative design [3], where cases were patients testing SARS-CoV-2 positive and controls were patients testing SARS-CoV-2 negative. We included patients aged 65 years and older belonging to the COVID-19 vaccine age-specific target groups at

time of swab collection, between 10 December 2020 and 31 May 2021. We excluded patients with missing age, patients in residential care homes, patients previously testing positive for SARS-CoV-2 (where information was known/reported), controls testing positive for seasonal coronaviruses and patients with missing COVID-19 vaccination status and/or date of vaccination. We included only those who were swabbed within 10 days (for investigation with RT-PCR) or 5 days (for investigation with rapid antigen tests) of symptom onset. In study sites where date of symptom onset was not available (one site) or had ≥ 25% of missing information (two sites), we imputed it as 3 days before the swab date, as 3 days was the median delay between onset and swab in the pooled data.

We defined a person as having received 'at least one dose of vaccine' if received at least one dose of vaccine ≥ 14 days before symptom onset, vaccinated with 'one dose only' if received only one of two recommended doses ≥ 14 days before symptom onset, and a person 'completely vaccinated' if received one dose of Janssen vaccine or the second dose of other vaccines ≥ 14 days before symptom onset.

<caption>**TABLE 1**</caption>

Characteristics of study sites participating in the primary care/outpatient I-MOVE-COVID-19 vaccine effectiveness study, Europe, December 2020-May 2021 (n = 9)

<table><thead><tr><th>Site</th><th>Comprehensive /sentinel</th><th>Primary care physician (PC) / community (Com)</th><th>Swab collection</th><th>Vaccines used in study population<sup>a</sup><br>Cominarty (C), Vaxzevria (V), Spikevax (S), Janssen (J)</th><th>Source of information<br>Electronic medical records (E), vaccine registry (VR), GP interview (GPI), patient questionnaire (P), other health databases, including national laboratory databases (H)</th><th>Laboratory tests used<br>RT-PCR (PCR), rapid antigen test (RAT)</th></tr></thead><tbody><tr><td>England</td><td>Sentinel</td><td>PC</td><td>At GP practice</td><td>C, V</td><td>E, VR</td><td>PCR</td></tr><tr><td>France</td><td>Sentinel</td><td>PC</td><td>At medical laboratory or at GP practice</td><td>C, V, S, J</td><td>GPI</td><td>PCR, RAT</td></tr><tr><td>Ireland</td><td>Sentinel</td><td>PC</td><td>At COVID-19 testing centre</td><td>C, V, S</td><td>VR, GP, H</td><td>PCR</td></tr><tr><td>Netherlands</td><td>Sentinel</td><td>PC</td><td>At GP practice</td><td>Information on vaccine type not collected</td><td>GPI</td><td>PCR</td></tr><tr><td>Portugal</td><td>Sentinel</td><td>PC</td><td>At COVID-19 testing centre</td><td>C, V, S</td><td>GPI, H, VR, E</td><td>PCR, RAT</td></tr><tr><td>Scotland</td><td>Sentinel</td><td>Com</td><td>At COVID-19 testing centre</td><td>C, V</td><td>P</td><td>PCR</td></tr><tr><td>Spain (three regions)</td><td>Sentinel</td><td>PC</td><td>At GP practice</td><td>C, V</td><td>GPI, E, VR</td><td>PCR, RAT</td></tr><tr><td>Spain (Navarra)</td><td>Comprehensive</td><td>PC</td><td>At GP practice</td><td>C, V, S, J</td><td>E, VR</td><td>PCR, RAT</td></tr><tr><td>Sweden</td><td>Sentinel</td><td>PC</td><td>At GP practice</td><td>C</td><td>GPI, H, VR</td><td>PCR</td></tr></tbody></table>

a: Cominarty (BNT162b2, BioNTech-Pfizer, Mainz, Germany/New York, United States); Com: community; COVID-19: coronavirus disease; E: electronic medical records; GP: general practice; GPI: general practitioner interview; H: other health databases, including national laboratory databases; J: Janssen (Ad26.COV2-S (recombinant), Janssen-Cilag International NV, Beerse, Belgium); P: patient questionnaire; PC: primary care physician; RT-PCR: real time reverse transcription-polymerase chain reaction; RAT: rapid antigen test; S: Spikevax (mRNA-1273, Moderna, Cambridge, US), US; V: Vaxzevria (ChAdOx1/nCoV-19, AstraZeneca, Cambridge, United Kingdom); VE: vaccine effectiveness; VR: vaccine registry.

<footnote>a Study population between 10 December 2020 and 31 May 2021. Other vaccines may have been used in these countries, but were not captured within this study.</footnote>
Persons were considered to be ‘unvaccinated’ if they had not received any vaccine or were vaccinated on the day that symptoms started or after symptom onset. Those receiving their first dose of vaccine < 14 days before symptom onset were excluded from the main analysis for VE of at least one dose or VE of one dose only. Those receiving their first dose of Janssen vaccine or second dose of other vaccines < 14 days before symptom onset were excluded from the VE analysis for complete vaccination. These persons were included in the analysis of VE by time since vaccination for vaccination either 1–4 days or 6–13 days before symptom onset.

In five study sites where technically feasible, the whole or partial genome of all or a random selection of viruses confirmed by PCR was sequenced. Two further study sites sequence viruses from confirmed PCR cases, but selection for sequencing was not random throughout the study period. Phylogenetic analysis was performed to identify the Phylogenetic Assignment of Named Global Outbreak (Pango) lineage based on the classification of 15 June 2021.

## Statistical analysis

We compared the odds of vaccination between cases and controls. We computed VE as 1 minus the OR, expressed as a percentage. We used logistic regression to model the OR, including study site as a fixed effect and month of swab taken in a crude analysis. In addition, in adjusted analyses, we included age group, sex and presence of at least one underlying chronic condition relevant to COVID-19 (diabetes, heart disease, chronic lung disease, immunodeficiencies).

We also conducted a secondary analysis excluding Scotland in view of differences with other protocols (see Supplementary Material), and sensitivity analyses excluding one study site with ca 25% of missing PCR/ RAT test results and study sites with imputed dates of onset. In further sensitivity analyses, we varied the imputed onset dates between 2 and 5 days before swab date. We measured VE up to the end of April 2021 to assess the effect of high vaccine coverage rates in older age groups as time progressed.

To avoid small sample bias, we did not present any analyses where there were five or fewer vaccinated cases or controls.

## Ethical statement

The planning, conduct and reporting of the studies was in line with the Declaration of Helsinki. Official ethical approval was not required if studies were classified as part of routine care/surveillance (i.e. in the Netherlands, Spain (three regions), England, Scotland and Ireland). Other study sites obtained local ethical approval from a national review board. This was the case for France (French Data Protection Agency (registration number CNIL#471393) and the French ethics research committee (‘Comité de Protection des Personnes’ – CPP)); Navarre (registration number

PI2020/45); Portugal (Ethics Committee of Instituto Nacional de Saúde Doutor Ricardo Jorge, no registration number given) and Sweden (registration number 2006/1040-31/2).

## Vaccine effectiveness results

### Main analysis

In the main analysis, we included 4,964 patients (Supplementary Figure S1), comprising 592 cases and 4,372 controls (Supplementary Figure S2).

Among them, 51% of cases (299/592) and 43% of controls (1,878/4,372) were aged 65–74 years (Supplementary Table S1). Among cases, 14% (84/592) were vaccinated with at least one dose and 9% (52/592) were vaccinated with one dose only of COVID-19 vaccine. Among those vaccinated with at least one dose, where vaccine product was known, 73% (61/83) were vaccinated with Comirnaty. Among controls, 46% (2,014/4,372) were vaccinated with at least one dose of COVID-19 vaccine and 20% (866/4,368) were vaccinated with one dose only of COVID-19 vaccine. Among those vaccinated with at least one dose, where vaccine product was known, 66% (1,327/1,998) were vaccinated with the Comirnaty vaccine.

There were 465 cases presenting in the seven study sites undertaking sequencing. Of those, 31 (7%) were sequenced and 27 (87%) of these belonged to the SARS-CoV-2 Alpha variant (B.1.1.7) of concern (Supplementary Table S2).

The adjusted VE for any vaccine for one dose only and complete vaccination against symptomatic infection were 62% (95% CI: 45–74) and 89% (95% CI: 79–94), respectively (Table 2). The VE for Comirnaty for one dose only and complete vaccination were 61% (95% CI: 39–75) and 87% (95% CI: 74–93), respectively. The VE for Vaxzevria for one dose only was 68% (95% CI: 39–83). We could not estimate VE for Vaxzevria for completed vaccination and any VE for Janssen and Spikevax due to small sample size.

The adjusted odds for having received one dose of any 2-dose COVID-19 vaccine was 14% greater among controls than among cases in 1–4 days between vaccination and onset and 12% and 30% for the Comirnaty and Vaxzevria vaccines, respectively (Table 3).

### Sensitivity analyses

Descriptive analyses and VE estimates of the secondary analysis with eight study sites are reported in Supplementary Tables S3, S4 and S5. The VE point estimate of one dose only of any COVID-19 vaccine was 6% lower compared with the main analysis, while the VE point estimate of complete vaccination was 2% lower.

Sensitivity analyses excluding specific study sites with different imputations for onset date and with a study period up to the end of April 2021 resulted in VE point
TABLE 2

Effectiveness of COVID-19 vaccination among participants aged 65 years and older in the primary care/outpatient I-MOVE-COVID-19 vaccine effectiveness study, Europe, December 2020-May 2021

<table><thead><tr><th colspan="4">Main analysis (Nine study sites)</th></tr><tr><th>Analysis type and vaccination status</th><th>Cases; vaccinated/ controls; vaccinated</th><th>Crude VE (95% CI)<sup>a</sup></th><th>Adjusted VE (95% CI)<sup>b</sup></th></tr></thead><tbody><tr><td>At least one dose<sup>c</sup></td><td>592; 84 / 4,372; 2,014</td><td>74 (64-80)</td><td>73 (63-81)</td></tr><tr><td>One dose only<sup>d</sup></td><td>560; 52 / 3,224; 866</td><td>62 (45-74)</td><td>62 (45-74)</td></tr><tr><td>Completely vaccinated<sup>e</sup></td><td>522; 14 / 3037; 679</td><td>88 (79-94)</td><td>89 (79-94)</td></tr><tr><th colspan="4">Comirnaty (BNT162b2, BioNTech-Pfizer, Mainz, Germany/New York, United States) vaccine</th></tr><tr><td>At least one dose<sup>c</sup></td><td>566; 61 / 3,672; 1327</td><td>73 (62-80)</td><td>74 (63-82)</td></tr><tr><td>One dose only<sup>d</sup></td><td>535; 30 / 2,778; 433</td><td>60 (38-74)</td><td>61 (39-75)</td></tr><tr><td>Completely vaccinated<sup>e</sup></td><td>519; 14 / 2,857; 512</td><td>85 (73-92)</td><td>87 (74-93)</td></tr><tr><th colspan="4">Vaxzevria (ChAdOx1/nCoV-19, AstraZeneca, Cambridge, United Kingdom) vaccine</th></tr><tr><td>At least one dose<sup>c</sup></td><td>523; 18 / 2,810; 465</td><td>75 (52-87)</td><td>74 (50-86)</td></tr><tr><td>One dose only<sup>d</sup></td><td>523; 18 / 2,687; 342</td><td>68 (41-83)</td><td>68 (39-83)</td></tr><tr><td>Completely vaccinated<sup>e</sup></td><td>Sample size too small</td><td>NA</td><td>NA</td></tr></tbody></table>

CI: confidence interval; COVID-19: coronavirus disease; NA: not applicable; VE: vaccine effectiveness.

TABLE 3

Odds ratio of COVID-19 vaccination by time since vaccination to symptom onset among participants receiving one dose only of 2-dose COVID-19 vaccines in the primary care/outpatient I-MOVE-COVID-19 vaccine effectiveness study, Europe, December 2020-May 2021

<table><thead><tr><th colspan="4">Main analysis (Nine study sites)</th></tr><tr><th>Analysis type and one dose<br>vaccination status</th><th>Cases / controls</th><th>OR<br>(95% CI)<sup>a</sup></th><th>AOR (95% CI)<sup>b</sup></th></tr></thead><tbody><tr><td colspan="4">Any COVID-19 vaccine (except Janssen (Ad26.COV2-S (recombinant), Janssen-Cilag International NV, Beerse, Belgium))</td></tr><tr><td>Unvaccinated</td><td>508/2,358</td><td>Ref</td><td>Ref</td></tr><tr><td>1-4 days<sup>c</sup></td><td>36/243</td><td>0.89 (0.60-1.31)</td><td>0.86 (0.58-1.27)</td></tr><tr><td>5-13 days<sup>d</sup></td><td>59/503</td><td>0.64 (0.47-0.89)</td><td>0.63 (0.45-0.87)</td></tr><tr><td>≥ 14 days<sup>e</sup></td><td>52/866</td><td>0.38 (0.26-0.55)</td><td>0.38 (0.26-0.55)</td></tr><tr><td colspan="4">Comirnaty (BNT162b2, BioNTech-Pfizer, Mainz, Germany/New York, United States) vaccine</td></tr><tr><td>Unvaccinated</td><td>506/2,352</td><td>Ref</td><td>Ref</td></tr><tr><td>1-4 days<sup>c</sup></td><td>27/169</td><td>0.92 (0.59-1.43)</td><td>0.88 (0.56-1.39)</td></tr><tr><td>5-13 days<sup>d</sup></td><td>50/366</td><td>0.70 (0.50-0.99)</td><td>0.68 (0.48-0.97)</td></tr><tr><td>≥ 14 days<sup>e</sup></td><td>30/433</td><td>0.40 (0.26-0.62)</td><td>0.39 (0.25-0.61)</td></tr><tr><td colspan="4">Vaxzevria (ChAdOx1/nCoV-19, AstraZeneca, Cambridge, United Kingdom) vaccine</td></tr><tr><td>Unvaccinated</td><td>505/2,345</td><td>Ref</td><td>Ref</td></tr><tr><td>1-4 days<sup>c</sup></td><td>6/56</td><td>0.71 (0.29-1.74)</td><td>0.70 (0.28-1.73)</td></tr><tr><td>5-13 days<sup>d</sup></td><td>3/102</td><td>Sample size too small</td><td>Sample size too small</td></tr><tr><td>≥ 14 days<sup>e</sup></td><td>18/342</td><td>0.32 (0.17-0.59)</td><td>0.32 (0.17-0.61)</td></tr></tbody></table>

CI: confidence interval; COVID-19: coronavirus disease; NA: not applicable; VE: vaccine effectiveness.

<footnote>a Adjusted by study site, month of swab taken (due to low numbers December and January were grouped as one category).</footnote>

<footnote>b Adjusted by study site, month of swab taken (due to low numbers December and January were grouped as one category), 10-year age group, sex. Due to substantial missing data on chronic conditions from one study site, the estimates were not adjusted by chronic condition.</footnote>

<footnote>c First dose of any COVID-19 vaccine received ≥ 14 days before onset.</footnote>

<footnote>d One of two recommended doses of COVID-19 vaccine received ≥ 14 days before onset. Excludes Janssen vaccine as it is a 1-dose vaccine.</footnote>

<footnote>e Second dose of COVID-19 vaccine received ≥ 14 days before onset, or first dose received ≥ 14 days before onset if Janssen vaccine. Eighteen cases and 465 controls received a second dose of any vaccine <14 days before onset. In the Comirnaty-specific analysis, 17 cases and 381 controls received a second dose of vaccine <14 days before onset.</footnote>

<footnote>a Adjusted by study site, month of swab taken (due to low numbers December and January were grouped as one category).</footnote>

<footnote>b Adjusted by study site, month of swab taken (due to low numbers December and January were grouped as one category), 10-year age group, sex. Due to substantial missing data on chronic conditions from one study site, the estimates were not adjusted by chronic condition.</footnote>

<footnote>c First dose of any COVID-19 vaccine received ≥ 14 days before onset.</footnote>

<footnote>d One of two recommended doses of COVID-19 vaccine received ≥ 14 days before onset. Excludes Janssen vaccine as it is a 1-dose vaccine.</footnote>

<footnote>e Second dose of COVID-19 vaccine received ≥ 14 days before onset, or first dose received ≥ 14 days before onset if Janssen vaccine. Eighteen cases and 465 controls received a second dose of any vaccine <14 days before onset. In the Comirnaty-specific analysis, 17 cases and 381 controls received a second dose of vaccine <14 days before onset.</footnote>
estimates varying within 4% of the primary VE esti-
mates (Supplementary table S6).

Discussion

Our results suggest that vaccination with one only
dose offered moderate protection (62%) against symp-
tomatic SARS-CoV-2 infection among adults aged 65
years and older consulting at primary care level, and
good protection (89%) among those who were com-
pletely vaccinated. Both the Comirnaty and Vaxzevria
vaccines provide protection after one dose and good
protection after two doses of Comirnaty. Sample size
was too low to evaluate two doses of Vaxzevria.

These results are consistent with reported VE esti-
mates against symptomatic COVID-19 infection among
older adults in community/outpatient settings, of
47-70% [4-6] among those vaccinated with one dose
and 85-96% [4-7] among fully vaccinated. Results are
slightly higher compared with a community-based
study among close contacts in Navarra, Spain, where
VE point estimates against symptomatic COVID-19
infection among those aged 60 years and older were
30% (95% CI: 10-45) among partially vaccinated and
77% (95% CI: 56-88) among fully vaccinated [8].
Differences could be explained by a multitude of fac-
tors, such as characteristics of the study population,
case definitions, differential virus exposures, vacci-
nation status definitions (including use of swab date
instead of date of symptom onset), vaccines used, cir-
culating variants and random variation.

We observed some effect from the vaccine (14%) among those vaccinated with one dose 1-4 days before symptom onset when no effect of the vaccine should be evident, although confidence intervals include 0%. This has also been observed by Lopez Bernal et al. [4], where a greater effect for the Vaxzevria vaccine compared with the Comirnaty vaccine was observed. This effect could be explained by an increase in SARS-CoV-2 testing among vaccinated controls, due to onset of systemic symptoms caused by the vaccine for a few days after vaccination [9]. Alternatively, persons with COVID-19 symptoms or contacts of cases may defer vaccination. We observed some vaccine effect (32%) among those vaccinated 5-13 days before symptom onset. This may be in part due to the imputation of onset date in three sites, which potentially led to the inclusion of persons vaccinated ≥14 days before symptom onset in this interval, where a vaccine effect is expected, or other unmeasured confounding, and warrants further investigation.

This is a multicentre study among settings with differ-
ent patient pathways in terms of location of swabbing,
vaccines used, sources of information and laboratory
investigations performed. When we excluded one study
site with purely community-based study including self-
collected swabs, this changed the VE of any COVID-19
vaccine by ≤6%.

Limitations include small sample sizes in some of the
study sites. However, a multicentre design to measure
VE in the context of different vaccines used and vac-
cine schedules can be a strength. We could not meas-
ure variant-specific VE due to the small proportion of
sequencing results. Measuring variant-specific VE is
an aim of our group in the near future as sequencing
capacity increases.

As vaccination rolls out, certain target groups for vacci-
nation are becoming highly vaccinated, e.g., at time of
writing the proportions of those aged 80 years and over
vaccinated with one and two doses were approaching
95-100% in some countries [10]. Those unvaccinated in
this target group may be an unusual population, with
potentially a different risk of infection or exposure to
the virus, thus violating core criteria of VE studies [11].

To check for this potential bias, we measured VE up to
the end of April and the results were the same com-
pared with the VE up to the end of May (Supplementary
Table S6). Future studies need to take this challenge
into account.

In three sites where previous SARS-CoV-2 infection was
documented, we excluded controls with previous infec-
tion. However, even in those sites, previous infection
is not always known, particularly with asymptomatic
infections, and persons with previous infection could
have been included among all study sites. This may
have introduced bias in our results if previous infection
influenced vaccination status.

In the main analysis, VE was not adjusted by presence
of chronic condition, due to a large amount of missing
data from one study site. In the secondary analysis,
results differed only by ≤1% after adjusting by presence
of chronic condition, indicating that chronic condition
may not be a confounder in this study population. In
all analyses month of swab and age were the strongest
confounders.

This is an observational study with potential further
selection and information biases than those men-
tioned above. However, the test-negative design used,
reduces bias due to healthcare seeking behaviour
[3,12-14].

Conclusions

COVID-19 vaccination provides substantial protection against COVID-19 presentation at primary care/outpatient level among those aged 65 and older, particularly after completed vaccination. As the vaccines do not provide 100% protection, vaccinated persons should continue to follow public health guidance, including hygiene and physical distancing measures. Next steps for the I-MOVE-COVID-19 VE study are to include more in-depth analysis of age and risk groups, VE by time since vaccination and increasing sequencing data of cases to measure variant-specific VE.
I-MOVE-COVID-19 primary care study team (in addition to authors above)

Nick Andrews, Public Health England, London, United Kingdom

Jamie Lopez Bernal, Public Health England, London, United Kingdom

Heather Whitaker, Public Health England, London, United Kingdom

Caroline Guerrisi - Sorbonne Université, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France

Titouan Launay - Sorbonne Université, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France

Shirley Masse - Laboratoire de Virologie, Université de Corse-Inserm, Corte, France

Sylvie van der Werf, Unité de Génétique Moléculaire des Virus à ARN, UMR 3569 CNRS, Université Paris Diderot SPC, Institut Pasteur, Paris; CNR des virus des infections respiratoires, Institut Pasteur, Paris, France

Vincent Enouf, Unité de Génétique Moléculaire des Virus à ARN, UMR 3569 CNRS, Université Paris Diderot SPC, Institut Pasteur, Paris; CNR des virus des infections respiratoires, Institut Pasteur, Paris, France

John Cuddihy, Health Service Executive-Health Protection Surveillance Centre, Dublin, Ireland

Adele McKenna, Health Service Executive-Health Protection Surveillance Centre, Dublin, Ireland

Michael Joyce, Irish College of General Practitioners, Dublin, Ireland

Cillian de Gascun, National Virus Reference Laboratory, University College Dublin, Dublin, Ireland

Joanne Moran, National Virus Reference Laboratory, University College Dublin, Dublin, Ireland

Ana Miqueleiz, Complejo Hospitalario de Navarra, Pamplona, Spain

Ana Navascués, Complejo Hospitalario de Navarra, Pamplona, Spain

Camino Trobajo-Sanmartín, Complejo Hospitalario de Navarra, Pamplona, Spain

Carmen Ezpeleta, Complejo Hospitalario de Navarra, Pamplona, Spain

Paula López Moreno, Servicio Navarro de Salud-Osasunbidea, Pamplona, Spain

Javier Gorricho, Servicio Navarro de Salud-Osasunbidea, Pamplona, Spain

Eva Ardanaz, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Fernando Baigorria, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain Aurelio Barricarte, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Enrique de la Cruz, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Nerea Egüés, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Manuel García Cenoz, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Marcela Guevara, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Conchi Moreno-Iribas, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Carmen Sayón, Instituto de Salud Pública y Laboral de Navarra—IdiSNA—CIBERESP, Pamplona, Spain

Verónica Gomez, Departamento de Epidemiología, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Baltazar Nunes, Departamento de Epidemiologia, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Rita Roquete, Departamento de Epidemiologia, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Adriana Silva, Departamento de Epidemiologia, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Aryse Melo, Departamento de Doenças Infeciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Inês Costa, Departamento de Doenças Infeciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Nuno Verdasca, Departamento de Doenças Infeciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Patrícia Conde, Departamento de Doenças Infeciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal

Diogo FP Marques, Public health Scotland, Glasgow, United Kingdom

Anna Molesworth, Public health Scotland, Glasgow, United Kingdom

Leanne Quinn, Public health Scotland, Glasgow, United Kingdom

Miranda Leyton, Public health Scotland, Glasgow, United Kingdom

Selin Campbell, Public health Scotland, Glasgow, United Kingdom

Janine Thoulass, Public health Scotland, Glasgow, United Kingdom

Jim McMenamin, Public health Scotland, Glasgow, United Kingdom

Ana Martínez Mateo, Subdirección General de Vigilancia y Respuesta a Emergencias de Salud Pública, Agencia de Salud Pública, Catalunya and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

Luca Basile, Subdirección General de Vigilancia y Respuesta a Emergencias de Salud Pública, Agencia de Salud Pública, Catalunya and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

Daniel Castrillejo, Servicio de Epidemiología, Dirección General de Salud Pública y Consumo, Melilla, Spain

Carmen Quiñones Rubio, Servicio de Epidemiología y Prevención Sanitaria, Dirección General de Salud Pública, Consumo y Cuidados, La Rioja, Spain

Concepción Delgado-Sanz, National Centre for Epidemiology, Institute of Health Carlos III, Madrid, Spain, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Institute of Health Carlos III, Madrid, Spain

Jesús Oliva, National Centre for Epidemiology, Institute of Health Carlos III, Madrid, Spain, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Institute of Health Carlos III, Madrid, Spain

Acknowledgments

Special thanks to Alain Moren, for critical review of the manuscript and fruitful discussions.

Special thanks also to the team of SARS-CoV-2 technicians of The Public Health Agency of Sweden for their hard work: Elin Arvesen, Eva Hansson Pihlainen and Nora Nid.

**Funding statement:** This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 101003673.
## Conflict of interest

Professor de Lusignan has received grants not directly relating to this work, from AstraZeneca, GSK, Sanofi, Seqirus and Takeda for vaccine-related research and has been a member of advisory boards for AstraZeneca, Sanofi and Seqirus.

## Authors' contributions

EK was involved in the original methodological design of the study (generic protocol). She contributes to the coordination of the I-MOVE-COVID-19 network and undertook the statistical analysis on which the research article is based. She led the manuscript writing, interpreted results and approved the final version of the manuscript.

MH and TJ contribute to the coordination of the primary care I-MOVE-COVID-19 network, helped interpret results, contributed to manuscript writing and approved the final version of the manuscript.

VSM and FP coordinate the I-MOVE virological analysis of the I-MOVE-COVID-19 network, helped interpret results, and read, contributed to and approved the final version of the manuscript.

All other named authors (IMB, NW, AMV, CM, LD, SdL, AM, AM, MB, IC, JLKM, SB, AL, JOD, RT, MdL, APR, MR, JC, MH, AF, LD, JC, RG, TE, CB, DS, TB, EMMO, JC, JE, RvGL, IK), including those in the I-MOVE-COVID-19 primary care study team, were responsible for the coordination of the study at the national/ regional level and contributed to developing the study site specific protocols. They were in charge of the data collection and management and validating the clinical and laboratory data published in this research article. They interpreted the results, read, contributed to and approved the final version of the manuscript.

MV initiated the original methodological design of the study and coordinates the I-MOVE-COVID-19 network. AMCR contributes to the coordination of the I-MOVE-COVID-19 network and MV and AMCR interpreted results, contributed to manuscript writing and approved the final version of the manuscript.

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