Abstract
Compared with individuals unvaccinated in the current and three previous influenza seasons, in 2021/22, influenza vaccine effectiveness at primary care level was 37% (95% CI: 16 to 52) for current season vaccination, regardless of previous doses, and 35% (95% CI: −3 to 45) for only previous seasons vaccination. Against influenza A(H3N2), estimates were 39% (95% CI: 16 to 55) and 24% (95% CI: −8 to 47) suggesting moderate effectiveness of current season vaccination and possible remaining effect of prior vaccinations.
Keywords: influenza, influenza vaccine, acute respiratory infection, case-control study, vaccine effectiveness, repeated vaccination
The influenza season 2021/22 in Spain and Europe was characterised by low incidence of cases, long duration, predominance of influenza A(H3N2), and sporadic circulation of influenza A(H1N1)pdm09 and B/Victoria viruses [1,2]. While interim estimates from Denmark and the United States showed a low influenza vaccine effectiveness (IVE) against influenza A(H3N2) virus at primary care level [3,4], the end of season IVE still needs to be determined. It also remains to be established if vaccination in previous influenza seasons modified the IVE.
We aimed to estimate the effectiveness of the influenza vaccinations received in the current and previous seasons in preventing laboratory-confirmed influenza among patients attending primary care in the 2021/22 season. These data may contribute to upcoming decisions for the 2023 vaccine strain selection for the southern hemisphere.
Setting and information sources
We performed a test-negative case–control study out in primary care in the Navarre region in northern Spain. In October and November 2021, the inactivated influenza vaccine was offered free of charge to all people aged 60 years or older and those aged 6 months or over with major chronic conditions. The trivalent adjuvanted vaccine (Chiromas, Sequirus, Siena, Italy) was mainly used in people older than 65 years and the tetravalent unadjuvanted vaccine (Vaxigrip Tetra, Sanofi Pasteur, Lyon, France) in the younger population.
Influenza vaccination status in the current and three previous seasons (2018/19 to 2021/22) was obtained from the online regional vaccination register [5]. Individuals were considered to be protected 14 days after vaccine administration.
From all acute respiratory infection (ARI) cases detected in primary care, nasopharyngeal and pharyngeal swabs were collected. Samples from patients who started symptoms in the previous 5 days were tested by antigen rapid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus 19 disease (COVID-19). Symptomatic patients with a negative antigen test result for SARS-CoV-2, or those who consulted more than 5 days after symptom onset, were tested by RT-PCR assay for SARS-CoV-2 and influenza viruses. Whole genome sequencing or partial sequencing by Sanger was done in some strains of each week. A phylogenetic analysis was performed using the HA1 subunit of the haemagglutinin gene.
Statistical analysis
The study population included ARI patients covered by the Navarre Health Service who were seen in primary care and tested for influenza virus from 22 November 2021 to 22 May 2022. We compared the vaccination status of laboratory-confirmed influenza patients (cases) and those who tested negative for influenza (controls). Nursing home residents and children younger than 9 years were excluded from the present study, as well as confirmed COVID-19 cases from the control group. However, patients with influenza and COVID-19 coinfection were included in the study.
Crude and adjusted odds ratios (OR) with their 95% confidence intervals (CI) were calculated using logistic regression. Adjusted models included sex, age group (9–24, 25–44, 45–64, 65–84 and ≥ 85 years), major chronic conditions, and month of swabbing. Although we performed the classical analysis including only current season vaccination, we considered as final IVE estimates those from models that included vaccination status in three previous seasons, using individuals unvaccinated in all seasons as reference category [6]. IVE was estimated as a percentage: (1–OR) x 100. Stratified analyses were performed by period (November–January and February–May), age groups (≤ 64 and ≥ 65 years) and in the target population.
A sensitivity analysis was performed including COVID-19 confirmed cases in the control group.
Vaccination effectiveness against laboratory-confirmed influenza
Among 10,655 ARI patients included, 644 (6%) were confirmed influenza cases and 20 of them were also confirmed COVID-19 cases. Influenza cases were detected over a long period (7 months) with peaks in December and March (Table 1). Among influenza cases, 513 were due to A(H3N2), 2 to A(H1N1), 1 to B, and 128 to A non-subtyped virus. Cases were compared with 10,011 control patients with a negative result for any influenza virus.
Table 1. Characteristics of the patients with acute respiratory infection included in the test negative case–control analysis, Navarre, Spain, 22 November 2021–22 May 2022 (n = 10,655).
| Variables | Laboratory-confirmed influenza cases n = 644 |
Influenza negative controls n = 10,011 |
p value | ||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Age groups (years) | |||||
| 9–24 | 213 | 33 | 1,674 | 17 | < 0.001 |
| 25–44 | 193 | 30 | 3,292 | 33 | |
| 45–64 | 132 | 21 | 3,204 | 32 | |
| 65–84 | 79 | 12 | 1,358 | 14 | |
| ≥ 85 | 27 | 4 | 483 | 5 | |
| Sex | |||||
| Male | 331 | 51 | 4,166 | 42 | < 0.001 |
| Female | 313 | 49 | 5,845 | 58 | |
| Major chronic conditions | |||||
| No | 421 | 65 | 6,422 | 64 | 0.530 |
| Yes | 223 | 35 | 3,589 | 36 | |
| Vaccination status in the current and three previous seasons | |||||
| Unvaccinated | 455 | 71 | 6,162 | 62 | < 0.001 |
| No current but any prior dose | 50 | 8 | 1,049 | 11 | |
| Current vaccine regardless of prior doses | 139 | 22 | 2,800 | 28 | |
| Month of sample collection | |||||
| Nov 2021 | 4 | 1 | 424 | 4 | < 0.001 |
| Dec 2021 | 188 | 29 | 5,416 | 54 | |
| Jan 2022 | 100 | 16 | 2,234 | 22 | |
| Feb 2022 | 59 | 9 | 835 | 8 | |
| Mar 2022 | 190 | 30 | 644 | 6 | |
| Apr 2022 | 74 | 12 | 258 | 3 | |
| May 2022 | 29 | 5 | 200 | 2 | |
All the 190 influenza A(H3N2) strains characterised were A/Bangladesh/4005/2020(H3N2)-like (Group 3C.2a1b.2a.2); however, while in the period November–January, 89% belonged to the subgroup (iii), in February–May, 84% corresponded to the subgroup (iv).
Compared with test-negative controls, there were higher proportions of influenza cases in those younger than 25 years of age and in males. Among cases, 22% had received the current season vaccine compared with 28% of controls (Table 1).
Considering only the current season vaccination, IVE was 34% (95% CI: 13 to 49). Compared with individuals unvaccinated in the current and three previous seasons, the preventive effect observed in those vaccinated in the current season regardless of previous doses was 37% (95% CI: 16 to 52), and in those unvaccinated in the current season who had been vaccinated in any previous season was 35% (95% CI: −3 to 45). Both estimates were 40% (95% CI: 17 to 57) and 24% (95% CI: −5 to 45) in patients younger than 65 years, 10% (95% CI: −76 to 54) and 16% (95% CI: −237 to 79) in people aged 65 years and older, and 34% (95% CI: 5 to 54) and 17% (95% CI: −37 to 49) in the target population i.e. all people aged 60 years or older and those aged 6 months or over with major chronic conditions (Table 2).
Table 2. Effectiveness of influenza vaccination in preventing laboratory-confirmed influenza at primary care level overall, by age groups and in the target population, Navarre, Spain, 22 November 2021–22 May 2022 (n = 10,655).
| Influenza vaccination status | Cases/controls n=644/10,011 |
Crude vaccine effectiveness % (95% CI) |
Adjusted vaccine effectiveness % (95% CI) |
|---|---|---|---|
| All patients | |||
| Current season only | |||
| Unvaccinated | 505/7,211 | Ref. | Ref. |
| Vaccinated | 139/2,800 | 19 (14 to 41) | 34 (13 to 49) |
| Current and three previous seasons | |||
| Unvaccinated | 455/6,162 | Ref. | Ref. |
| No current but any prior dose | 50/1,049 | 35 (13 to 52) | 35 (–3 to 45) |
| Current vaccine regardless of prior doses | 139/2,800 | 33 (18 to 45) | 37 (16 to 52) |
| Aged ≤ 64 years | |||
| Current season only | |||
| Unvaccinated | 490/6,895 | Ref. | Ref. |
| Vaccinated | 48/1,275 | 47 (28 to 61) | 38 (14 to 55) |
| Current and three previous seasons | |||
| Unvaccinated | 443/5,961 | Ref. | Ref. |
| No current but any prior dose | 47/934 | 32 (8 to 50) | 24 (–5 to 45) |
| Current vaccine regardless of prior doses | 48/1,275 | 49 (31 to 63) | 40 (17 to 57) |
| Age ≥ 65 years | |||
| Current season only | |||
| Unvaccinated | 15/316 | Ref. | Ref. |
| Vaccinated | 91/1,525 | – 26 (–120 to 28) | 7 (–72 to 49) |
| Current and 3 previous seasons | |||
| Unvaccinated | 12/201 | Ref. | Ref. |
| No current but any prior dose | 3/115 | 56 (–58 to 88) | 16 (–237 to 79) |
| Current vaccine regardless of prior doses | 91/1,525 | 0 (–86 to 46) | 10 (–76 to 54) |
| Target populationb | |||
| Current season only | |||
| Unvaccinated | 143/2,091 | Ref. | Ref. |
| Vaccinated | 116/2,221 | 24 (2 to 41) | 32 (3 to 52) |
| Current and 3 previous seasons | |||
| Unvaccinated | 121/1,656 | Ref. | Ref. |
| No current but any prior dose | 22/435 | 31 (–10 to 57) | 17 (–37 to 49) |
| Current vaccine regardless of prior doses | 116/2,221 | 28 (7 to 45) | 34 (5 to 54) |
CI: confidence interval; Ref.: reference.
a Vaccine effectiveness adjusted by age groups (9–24, 25–44, 45–64, 65–84 and ≥ 85 years), sex, presence of major chronic conditions, and month.
b Target population includes people aged 60 years or older and those aged 6 months or over people with major chronic conditions.
Among all ages, the vaccine effectiveness against influenza A(H3N2) was 39% (95% CI: 16 to 55) for current season vaccination regardless of prior doses and 24% (95% CI: –8 to 47) for those unvaccinated in the current season but vaccinated in any previous season. Current season IVE regardless of prior doses was 45% (95% CI: 20 to 62) in the November–January period and 23% (95% CI: –17 to 49) in February–May (p = 0.357), while people unvaccinated in the current season and vaccinated in previous seasons increased their IVE from 6% (95% CI: –43 to 38) to 42% (95% CI: 3 to 65) (Table 3).
Table 3. Effectiveness of influenza vaccination in preventing laboratory-confirmed influenza at primary care by calendar period and against A(H3N2) subtype, Navarre, Spain, 22 November 2021–22 May 2022 (n = 10,655 patients).
| Influenza vaccination status | Cases/controls | Crude vaccine effectiveness % (95% CI) |
Adjusted vaccine effectivenessa
% (95% CI) |
|---|---|---|---|
| Nov 2021–Jan 2022 | |||
| Current season only | |||
| Unvaccinated | 250/1,142 | Ref. | Ref. |
| Vaccinated | 102/795 | 41 (25 to 54) | 44 (20 to 61) |
| Current and three previous seasons | |||
| Unvaccinated | 217/958 | Ref. | Ref. |
| No current but any prior dose | 33/184 | 21 (–18 to 47) | 6 (–43 to 38) |
| Current vaccine regardless of prior doses | 102/795 | 43 (27 to 56) | 45 (20 to 62) |
| Feb–May 2022 | |||
| Current season only | |||
| Unvaccinated | 255/6,069 | Ref. | Ref. |
| Vaccinated | 37/2,005 | 56 (38 to 69) | 17 (–26 to 45) |
| Current and three previous seasons | |||
| Unvaccinated | 238/5,204 | Ref. | Ref. |
| No current but any prior dose | 17/865 | 57 (29 to 74) | 42 (3 to 65) |
| Current vaccine regardless of prior doses | 37/2,005 | 60 (43 to 72) | 23 (–17 to 49) |
| A(H3N2) subtype | |||
| Current season only | |||
| Unvaccinated | 397/7,211 | Ref. | Ref. |
| Vaccinated | 116/2,800 | 25 (7 to 39) | 36 (13 to 53) |
| Current and three previous seasons | |||
| Unvaccinated | 357/6,162 | Ref. | Ref. |
| No current but any prior dose | 40/1,049 | 34 (8 to 53) | 24 (–8 to 47) |
| Current vaccine regardless of prior doses | 116/2,800 | 28 (11 to 42) | 39 (16 to 55) |
CI: confidence interval; Ref.: reference.
a Vaccine effectiveness adjusted by age groups (9–24, 25–44, 45–64, 65–84 and ≥ 85 years), sex, presence of major chronic conditions and month.
In the sensitivity analysis including COVID-19 positive patients in the control group, the IVE estimates were slightly lower (Supplementary Tables S1–S3).
Discussion
Our results suggest a moderate IVE for the 2021/22 seasonal influenza vaccine of 37% against all confirmed influenza cases and of 39% influenza A(H3N2) cases, while no significant effect was observed in people aged 65 years and older at the primary care level in Navarre, Spain. Interestingly, our results also show that people vaccinated in previous seasons but not in the current season could retain some level of protection that reached statistical significance in the February–May period.
These IVE estimates were slightly higher than the in-season ones reported from Denmark and the United States [3,4]. All influenza A(H3N2) viruses characterised in the 2021/22 season in Navarre were A/Bangladesh/4005/2020-like (3C.2a1b.2a.2), which did not match the A/Cambodia/e0826360 (3C.2a1b.2a.1) vaccine component [7]. The November–January period was dominated by the subgroup (iii), while the February–May period was dominated by the subgroup (iv), as has been observed in other European countries [7]. Although it was not statistically significant, the current season IVE seemed to decline and the IVE of previous doses seemed to increase, suggesting a possible difference in affinity of both subgroups for the components of previous vaccines.
Moderate or low IVE is frequently observed in seasons with influenza A(H3N2) dominance [6,8]; furthermore, the very low influenza circulation in the 2020/21 season limited the information that supported the selection of the 2021/22 season vaccine composition [9].
Vaccines received in previous seasons may retain some preventive effect and modify the effect of the current season vaccine [6,8,10]. From the individual perspective, the total preventive benefit is the combined result of vaccinations received in the current and previous seasons. Our results suggest that strains included in vaccines of previous seasons may retain some effect against the influenza virus that circulated in the 2021/22 season. Furthermore, our IVE point estimates were slightly higher when the vaccination history was considered in the analyses.
Strengths of this study are that the comprehensive virological surveillance provided a sufficient number of cases in a season with low influenza activity and that COVID-19 confirmed cases were excluded from the control group in the main analysis to avoid possible bias [11]. To avoid biases due to vaccination information [8], the vaccination status was obtained from the regional vaccination register [5], and the study was limited to the population with stable residence in the region.
This study also has some limitations. The statistical power was limited in some analyses such as in older people or to assess changes in the IVE over time. Some level of selection bias cannot be fully excluded but it was reduced by recruiting laboratory-confirmed cases and controls in the same setting before either patient or physician were aware of laboratory results [12]. Since most COVID-19 rapid antigen test-positive patients were not tested by RT-PCR, coinfection may be underrepresented in the main analysis. This study was performed in only one region and in the special context of the COVID-19 pandemic; therefore, caution should be taken in generalising these results to other settings.
Conclusion
Our results suggest moderate effectiveness of the 2021/22 influenza season vaccine in preventing influenza overall and, specifically, influenza A(H3N2) in outpatients, while no significant effect was observed in people older than 65 years of age and above. A possible remaining effect of previous influenza vaccine doses was seen in patients unvaccinated during the current season. Influenza vaccination provided an overall benefit even in a season with mismatch between vaccine components and the circulating influenza virus.
Statements
Ethical statement: This study was approved by the Navarre’s Ethical Committee for Clinical Research (PI2020/45), which waived the requirement of obtaining informed consent.
Funding statement: This study was supported by the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Network funded by the European Centre for Disease Prevention and Control (RS/2021/DRP/12984) and by the Instituto de Salud Carlos III with the European Regional Development Fund (PI20/01323, CM19/00154, and INT21/00100).
Acknowledgements
We thank the professionals in primary healthcare in Navarre.
Supplementary Data
Conflict of interest: None declared.
Authors’ contributions: IM-B, IC, and JC designed the study and coordinated the activities. IM-B undertook the statistical analysis. AM, AN, FP, MF-H, and CE were responsible of the virological analysis and the interpretation of laboratory results. CT-S, EA, FE, and CB participated in the data collection. IM-B, IC and JC wrote the draft manuscript, and all authors revised and approved the final version.
References
- 1.Sistema de Vigilancia de la Gripe en España. Informe semanal de Vigilancia de la Gripe en España. Semana 20/2022 N° 81. [Weekly report of the influenza surveillance system in Spain 20/2022. N° 81]. Madrid: Instituto de Salud Carlos III. [Accessed: 31 May 2022]. Spanish. Available from: http://vgripe.isciii.es/inicio.do
- 2. Melidou A, Ködmön C, Nahapetyan K, Kraus A, Alm E, Adlhoch C, et al. Members of the WHO European Region influenza surveillance network. Members of the WHO European Region influenza surveillance network that contributed virus characterisation data . Influenza returns with a season dominated by clade 3C.2a1b.2a.2 A(H3N2) viruses, WHO European Region, 2021/22. Euro Surveill. 2022;27(15):2200255. 10.2807/1560-7917.ES.2022.27.15.2200255 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Emborg HD, Vestergaard LS, Botnen AB, Nielsen J, Krause TG, Trebbien R. A late sharp increase in influenza detections and low interim vaccine effectiveness against the circulating A(H3N2) strain, Denmark, 2021/22 influenza season up to 25 March 2022. Euro Surveill. 2022;27(15):2200278. 10.2807/1560-7917.ES.2022.27.15.2200278 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Chung JR, Kim SS, Kondor RJ, Smith C, Budd AP, Tartof SY, et al. Interim Estimates of 2021-22 Seasonal Influenza Vaccine Effectiveness - United States, February 2022. MMWR Morb Mortal Wkly Rep. 2022;71(10):365-70. 10.15585/mmwr.mm7110a1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Aguilar I, Reyes M, Martínez-Baz I, Guevara M, Albéniz E, Belza M, et al. Use of the vaccination register to evaluate influenza vaccine coverage in seniors in the 2010/11 influenza season, Navarre, Spain. Euro Surveill. 2012;17(17):20154. 10.2807/ese.17.17.20154-en [DOI] [PubMed] [Google Scholar]
- 6. Martínez-Baz I, Navascués A, Casado I, Aguinaga A, Ezpeleta C, Castilla J. Simple models to include influenza vaccination history when evaluating the effect of influenza vaccination. Euro Surveill. 2021;26(32):2001099. 10.2807/1560-7917.ES.2021.26.32.2001099 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.European Centre for Disease Prevention and Control (ECDC). Influenza virus characterisation. Summary Europe, March 2022. Stockholm: ECDC. [Accessed: 31 May 2022]. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/Influenza-characterisation-report-march-2022.pdf
- 8. McLean HQ, Thompson MG, Sundaram ME, Meece JK, McClure DL, Friedrich TC, et al. Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons. Clin Infect Dis. 2014;59(10):1375-85. 10.1093/cid/ciu680 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.World Health Organization. Recommended composition of influenza virus vaccines for use in the 2021- 2022 northern hemisphere influenza season. February 2021. [Accessed: 29 June 2022]. Available from: https://cdn.who.int/media/docs/default-source/influenza/202102_recommendation.pdf?sfvrsn=8639f6be_3&download=true
- 10. Ramsay LC, Buchan SA, Stirling RG, Cowling BJ, Feng S, Kwong JC, et al. The impact of repeated vaccination on influenza vaccine effectiveness: a systematic review and meta-analysis. BMC Med. 2019;17(1):9. 10.1186/s12916-018-1239-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Doll MK, Pettigrew SM, Ma J, Verma A. Effects of confounding bias in COVID-19 and influenza vaccine effectiveness test-negative designs due to correlated influenza and COVID-19 vaccination behaviors. Clin Infect Dis. 2022;ciac234.; Online ahead of print. [DOI] [PMC free article] [PubMed]
- 12. Valenciano M, Kissling E, Ciancio BC, Moren A. Study designs for timely estimation of influenza vaccine effectiveness using European sentinel practitioner networks. Vaccine. 2010;28(46):7381-8. 10.1016/j.vaccine.2010.09.010 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.