HUMAN VACCINES & IMMUNOTHERAPEUTICS

2023, VOL. 19, NO. 3, 2263219

https://doi.org/10.1080/21645515.2023.2263219

BRIEF REPORT

End of season 2022/2023 quadrivalent influenza vaccine effectiveness in preventing

influenza in primary care in Portugal
Irina Kislaya a, Ana Rita Torres a, Licínia Gomesb, Aryse Melob, Ausenda Machado a, Camila Henriquesb,
Nuno Verdascab, Raquel Guiomar b, Ana Paula Rodrigues a, and National Influenza Surveillance Network*
a
Departamento de Epidemiologia, Instituto Nacional de Saúde Doutor Ricardo Jorge IP (INSA, IP), Lisboa, Portugal; bDepartamento de Doenças
Infeciosas, Instituto Nacional de Saúde Doutor Ricardo Jorge IP (INSA, IP), Lisboa, Portugal

ABSTRACT ARTICLE HISTORY

Using a test-negative case–control design, we aim to estimate influenza vaccine effectiveness (VE) against Received 5 April 2023
medically attended laboratory-confirmed influenza in Portugal in 2022/2023 season. Between week 41/ Revised 1 September 2023
2022 and week 14/2023, data on 592 patients with influenza-like illness aged 18 or more years old were Accepted 21 September 2023
collected by the national sentinel influenza surveillance system in primary care settings. Of those, 218 KEYWORDS
were positive for influenza and 374 were negative controls. We estimated seasonal influenza VE as Vaccine effectiveness;
(1-odds ratio)*100% of being vaccinated in laboratory-confirmed influenza cases vs. negative controls influenza; primary care;
using logistic regression model adjusted for age group, sex, presence of chronic conditions, and month of Portugal; A(H3N2)
symptoms onset. The seasonal VE was 59.3% (95% confidence interval (CI): 27.3 to 77.3) against any
laboratory-confirmed influenza and not statistically significant 44.5% (95% CI: −5.6 to 70.8) against
influenza A (H3N2). In the 2022/2023 season, characterized by early and low influenza activity and
predominant A (H3N2) circulation, vaccination provided a moderate protection against medically
attended laboratory-confirmed influenza in primary care.

Introduction Portugal and vaccine coverage reached 75% among those

aged 65 or more years old.2
Vaccination is a key public health intervention to mitigate
2022/2023 influenza season was characterized by
influenza-associated illnesses and their complications. 2022/
a predominance of influenza A (H3N2) (77.9%), and sporadic
2023 influenza vaccination campaign in Portugal started on
circulation of influenza A (H1N1) pdm09 (12.7%) and influ­
week 36/2022, targeting those with a high risk of exposure and
enza B viruses (9.3%).3
post-infection severe outcomes. They included individuals Additionally, the epidemic influenza season occurred
aged 65 or more years old, pregnant women, individuals with between week 42/2022 and week 01/2023 being the earliest
underlying chronic conditions, health professionals and other seasonal influenza epidemic registered in Portugal. Epidemic
care providers, and those living in long-term care facilities.1 peak occurred around week 46/2022, had low intensity, and
Seasonal influenza vaccines available in the 2022/2023 season mainly affected children and young adults. The number of
included inactivated quadrivalent vaccines Fluarix Tetra® and influenza patients admitted to ICU was lower than in other
Vaxigrip Tetra®. The high-dose quadrivalent vaccine Efluelda® seasons, and there was no excess mortality during the 2022/
was available for residents in long-term care facilities. The 2023 influenza season.2 Circulating viruses were genetically
vaccine was offered free of charge to the target population and antigenically similar to vaccine strains.
and co-inoculated at vaccination centers in parallel with the Within the established Portuguese national immunization
COVID-19 vaccine seasonal booster dose. By week 17/2023, 2 program governance model, the National Health Institute
388 129 doses of influenza vaccine were administered in Doutor Ricardo Jorge is responsible for virological surveillance

CONTACT Irina Kislaya [email protected] Departamento de Epidemiologia, Instituto Nacional de Saúde Doutor Ricardo Jorge, Av. Padre Cruz, Lisboa 1649-
016, Portugal.
*National Influenza Surveillance Network members: Joana Catarina Fonseca Cirne, Margarida Brito Rosa, Susana Gomes Corte-Real, Maria Elvira Pinto Costa Silva, Ana
Maria da Conceição Ernesto, Isabel Tomás, Margarida Moreira, Arazanzu Souto, Ana Esperanza Fuertes Marcos, Rui Nogueira, Carlos Manuel Fernandes Pereira Alves,
Elisabete Pinto Borges Valério, Maria Teresa Libório, Vera Gaspar Costa, Rui Jorge Santos, Isabel Maria Festas Alves Pratas, Ana Paes de Vasconcellos, Valter Silva, Ana
Sofia Brandão Oliveira Gomes, Daniela Duarte Silva, Tiago Miguel Rodrigues Vilarinho, Graça Pacheco Coito, Inês Coimbra do Vale, Catarina Lírio Vitorino, Maria da
Conceição Fraga da Costa, Antony Fernandes Nogueira, Bárbara Gonçalves, Ana Catarina Cardoso de Almeida, Teresa Assunção, Ana Marques da Silva, Ana R. Mota,
Cristiana Vilaça Fernandes, Félix Rabunal, Isabel Margarida Borralheiro, Cláudia Souza, Susana C. Fernandes, Jorge Quintas, Rita Crisóstomo, Filipa Quinteiros, Natividad
Gavira Galán, Sara Teixeira, Ana Sardo, Daniela Emílio, Vanessa Guerreiro, João Gonçalves Estevens, Ana Rita Costa, Alexandre Coelho, Carolina Caetano, Sara Martins,
Carla Martins, Helder Batista, Luísa Carvalho, Luís Paulo Costa, Gonçalo Pimentel , Cecília Shinn, Leonor Troni, Raquel Baptista Leite, Maria João Freitas Domingues,
Beatriz Maria Mota Almeida, Ana Monteiro, Filomena Barroso, Helena Cabral, Paula Meireles, Ana Sara Gomes Silva, Mariana Rio Sousa Ramos, Vitória Aleixo, Susana
Pires da Silva, Palmira Caldas, João Moura, Nuno Miguel Figueiras Alves, Cecília Abreu, Cláudia Sofia Graça Junqueira, Carla Patrícia Costa Campos, Cláudia Ferreira.
I.Kislaya is currently affiliated with Department of Infectious Diseases Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
AR Torres is currently affiliated with Public Health Functions Unit, European Centre for Disease Prevention and Control, Stockholm, Sweden
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2263219.
© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 I. KISLAYA ET AL.

of vaccine-preventable diseases and implementation of vaccine ratio of being vaccinated in RT-PCR influenza-positive cases vs
effectiveness and impact studies,4 including influenza vaccine influenza-negative controls, obtained through a logistic regression
effectiveness studies.5 Influenza vaccine effectiveness estimates model adjusted for age group, sex, and presence of chronic con­
are important to inform national public health policy and may ditions (at least one among diabetes, asthma, or other chronic
contribute to upcoming decisions for vaccine strain selection respiratory diseases, cancer, chronic renal disease, hypertension
for the next season at the international level. or other chronic cardiovascular disease, obesity, chronic hepatic
This study aims to estimate the seasonal influenza vaccine disease, neuromuscular disease, and immunodeficiency), and
effectiveness in preventing laboratory-confirmed influenza in month of symptoms onset. Vaccine effectiveness was estimated
adult patients attending primary care, using data from the against all influenza and A (H3N2) subtypes, predominant in the
national influenza surveillance system in 2022/2023 season 2022/2023 early season. The significance level was set at 5%.
(week 41/2022 to week 14/2023). The study was conducted in compliance with the Helsinki
Declaration and national data protection legal and ethical
requirements. Data were collected under the surveillance proto­
Materials and methods
col, which has specific approvals from the Ethical Committee
A test-negative case – control study was developed5,6 relying on and the Data Protection Officer. The study protocol was
data collected by the national sentinel influenza surveillance updated in 2022/2023 and approved by the Ethics Committee
system, which includes 76 primary health-care units on of the INSA on 2022, December, 14th, and the INSA data
Portugal Mainland. Each sentinel general practitioner system­ protection officer on 2023, January, 26th. The requirement for
atically recruited up to five Influenza-Like Illness (ILI) patients written informed consent was waived by the Ethics Committee.
per week from whom nasopharyngeal swabs, clinical and epide­ Oral informed consent was taken from participants. The study
miological information were collected. Patients were recruited guideline, distributed to the Sentinel General Practitioners
according to the European ILI case definition, i.e., with sudden included the detailed procedure to inform patients about the
onset of at least one systemic (fever or feverishness, malaise, study´s objectives and implications and ask for their consent.
headache, myalgia) and one respiratory symptom (cough, sore
throat, shortness of breath). All data were collected during the
Results
general practitioner’s appointment either by asking the patients
or through a health registry consultation. Between week 41/2022 and week 14/2023, a total of 848
Samples from all recruited ILI patients were analyzed at the patients aged 18 or more years old were notified by the
National Reference Laboratory for Influenza and other respira­ national sentinel influenza surveillance system. Of those, 592
tory viruses for the detection of influenza (type), SARS-CoV-2, had information on clinical symptoms compatible with the ILI
and RSV, using a commercial RT-PCR assay Allplex™ SARS- case definition and vaccination status and were included in the
CoV-2/FluA/FluB/RSV (ASFR, Seegene Technologies Inc; analysis (Figure 1).
Seoul, South Korea). Subtyping of influenza A (H3N2 and The weekly distribution of ILI patients (influenza-positive
H1pdm09) and determination of the lineage of influenza cases and influenza-negative controls) included in the analysis
B (Victoria and Yamagata) were performed by adapting in- is shown in Figure 2. Overall, of laboratory-confirmed influ­
house RT-PCR. Genetic characterization of influenza virus was enza infections, 76.2% (n = 166) were A (H3N2), 14.2% (n =
performed based on the subunit 1 of hemagglutinin (HA1). 31) were A (H1N1) pdm09 and 9.6% (n = 21) were influenza
Those samples that presented CT value < 25 were selected to be B (Victoria lineage). Among influenza-negative ILI controls,
sequenced by NGS (Illumina) methodology. Sequences were SARS-CoV-2, was the most prevalent virus identified (20.3%)
analyzed using the INSaFLU pipeline (https://insaflu.insa.pt/), followed by Rhinovirus (17.1%). In addition, during the 2022/
and phylogenetic trees were built using Nextstrain (https:// 2023 season, in 5.6% of the influenza-negative controls multi­
nextstrain.org/). ple infections were detected (Table S1).
Cases were defined as ILI patients with positive RT-PCR A total of 214 influenza viruses were genetically character­
results for influenza. Controls were defined as those with ized. The characterized influenza A (H3N2) was clustered in
laboratory-negative results for influenza. Both cases and con­ three different clades: 3C.2a1b.2a.2b (2b), 3C.2a1b.2a.2a.1b
trols were considered vaccinated for influenza if the influenza (2a.1b), 3C.2a1b.2a.2a.3a.1 (2a.3a.1). The first one was the
vaccine uptake in the 2022/2023 season occurred 14 days predominant clade circulating in Portugal during 2022/2023
before the symptoms onset. season (Figure S1). The clades 6B.1A.5a.2a (5a.2a) and
The following exclusion criteria were established: i) not ful­ 6B.1A.5a.2a.1 (5a.2a.1) were identified in similar proportions
filling the ILI case definition; ii) being vaccinated during the 14 among the characterized influenza A (H1N1) pdm09 virus.
days prior to the onset of the symptoms; iii) controls recruited Regarding influenza B/Victoria, all the characterized viruses
before the first influenza case; iv) missing information regarding were clustered in clade V1A.3a.2.
vaccination status and date of symptoms onset; v) more than 7 The distribution of lab-confirmed influenza-positive ILI
days between symptoms onset date and swabbing date. cases by sex, age group, and presence of chronic conditions
Absolute and relative frequencies were used to describe the was statistically different from the negative controls (Table 1).
study participants. Characteristics of influenza-positive ILI Influenza-positive cases were younger than influenza-negative
patients (cases) were compared to influenza-negative controls controls and had a higher proportion of males (38.1% vs.
using the chi-square test. Influenza vaccine effectiveness was 25.9%). Chronic conditions were more frequent among con­
estimated as VE = (1- OR) *100%, where OR stands for odds trols (32.6% vs.20.6%). Variation by month of symptoms onset
 HUMAN VACCINES & IMMUNOTHERAPEUTICS 3

Figure 1. Participants exclusion flowchart.

Figure 2. Weekly distribution of laboratory-confirmed influenza-positive ILI cases and influenza-negative controls, Portugal, 2022/2023 season.

was significant between cases and controls, with a higher Discussion

number of cases was detected earlier in the season
Using data collected by the Portuguese influenza sentinel
(November, 44.5% vs.26.5%).
Influenza vaccine effectiveness in the adult population (18+ surveillance network, we estimated 2022/2023 end-of-
years old) was 59.3% (27.3 to 77.3) against laboratory- season vaccine effectiveness against laboratory-confirmed
confirmed influenza attended in primary care (both A and B) influenza in a primary care setting for the adult population
and 44.5% (−5.6 to 70.8) against A (H3N2) subtype, predomi­ ranging from 44.5% for A (H3N2) subtype to 59.3% for
nant in Portugal in 2022/23 season (Table 2). any influenza.
4 I. KISLAYA ET AL.

Table 1. Characteristics of laboratory-confirmed influenza cases and influenza-negative controls, Portugal, week 41/2022-week 14/2023.
Influenza-negative
Laboratory-confirmed influenza cases (n = 218) controls (n = 374)

Characteristics n % n % p-value
Age group (years) p = .009
18–44 123 56.4 184 49.2
45–64 82 37.6 138 36.9
≥65 13 6.0 52 13.9
Sex p = .002
Female 135 61.9 277 74.1
Male 83 38.1 97 25.9
Any chronic condition* p = .002
No 173 79.4 252 67.4
Yes 45 20.6 122 32.6
Month of symptoms onset p < .001
October 20 9.2 72 19.3
November 97 44.5 99 26.5
December 53 24.3 71 19.0
January 22 10.1 78 20.9
February 12 5.5 29 7.8
March 10 4.6 20 5.4
April 4 1.8 5 1.3
*diabetes type 1, diabetes type 2, hypertension, cardiovascular disease (excluding hypertension), chronic renal disease, chronic liver disease, neuromuscular
disease, immunodeficiency (congenital or acquired), obesity, asthma under medical treatment, chronic respiratory disease (excluding asthma), cancer.

Table 2. Interim influenza vaccine effectiveness against any influenza and A (H3N2) influenza, Portugal, week 41/2022-week 14/2023.
Negative controls
Laboratory-confirmed influenza cases n (%) n (%)

Vaccinated Unvaccinated Vaccinated Unvaccinated VE (%)* 95% CI

Any influenza 20 (9.2) 198 (90.8) 79 (21.2) 295 (78.9) 59.3 (27.3 to 77.3)
A(H3N2) 19 (11.4) 148 (88.7) 79 (21.2) 295 (78.9) 44.5 (−5.6 to 70.8)
*adjusted by age group, sex, chronic condition, and month of symptoms onset. VE: vaccine effectiveness; 95% CI: 95% confidence interval.

Estimates of VE obtained in this study were similar to early Among the study strengths we should mention test-
2022/2023 season estimates in Canada (58–59%) and the USA negative case–control design, which is frequently used in
(54–60%),7,8 countries also characterized by predominant influenza vaccine effectiveness studies as it has the advan­
A (H3N2) circulation, although our estimates against influ­ tage of control for selection bias related to the outcome
enza A (H3 N2) were not statistically significant, probably due and minimizes bias by health-seeking behavior. All labora­
to lower sample size. tory analyses were performed at the National Reference
When comparing to other seasons, dominated by Laboratory for Influenza and other respiratory viruses
A (H3N2), 2022/2023 seasonal A (H3N2) VE obtained in using high-sensitivity and high-specificity RT-PCR assays,
Portugal was higher compared to the end of 2021/2022 season so we expect the misclassification of outcome is expected
VE reported by I-MOVE network in Europe6 and Flu VE to be residual. Information on vaccination status was col­
Network in the USA.9 lected by the general practitioners and was retrieved from
Genetic analysis has shown that the circulating strains in health registries, so we expect the measure of the main
Portugal were grouped into three different clades for influ­ exposure also to be accurate.
enza A (H3N2), two different clades for influenza Our study has several limitations. The low intensity of
A (H1N1) pdm09 and one unique clade for influenza B/ influenza activity in the 2022/2023 season limited the study
Victoria. Despite some genetic diversity, influenza- sample size. Due to the small sample size, we were not able to
characterized viruses were antigenically similar to the estimate influenza VE by age group and presence of chronic
2022/2023 vaccine strains. Antigenic results also indicated condition as well as against A (H1N1) pdm09 and B influenza
that circulating influenza A (H3N2) and B/Victoria were subtypes and we acknowledge this limited the power to obtain
antigenically similar to the vaccine strains. Moreover, influ­ significant estimates against influenza A (H3N2). Considering
enza circulation occurred early in the season, very close to the differences in age, sex and chronic conditions between
the vaccination campaign when the population had higher cases and controls, vaccine effectiveness estimates were
levels of vaccine-induced protection,10 which could explain adjusted by potential confounders, however some residual
the higher VE estimates when compared to previous late confounding might persist, as the surveillance system collects
seasons. It is also interesting to note that this influenza information on a limited number of confounders.
season, had lower intensity and impact on ICU hospitaliza­ In conclusion, our results suggest that seasonal influenza
tion and in mortality than observed in previous A (H3N2) vaccine effectiveness confers moderate protection against
influenza seasons laboratory-confirmed influenza in a primary care setting.
 HUMAN VACCINES & IMMUNOTHERAPEUTICS 5

Disclosure statement https://www.insa.min-saude.pt/category/informacao-e-cultura-

cientifica/publicacoes/atividade-gripal/.
No potential conflict of interest was reported by the author(s). 4. Portaria n.o 248/2017, de 4 de agosto | DRE [Internet]; [Accessed
2023 Jan 11]. https://dre.pt/dre/detalhe/portaria/248-2017-
107951592.
5. Machado A, Kislaya I, Nunes B, Rodrigues AP, Guiomar R.
Funding Moderate influenza vaccine effectiveness in a B mismatch season:
The part of the data of the study was originally collected as part of the preliminary results from the 2017/2018 season in Portugal.
project “Vaccine effectiveness against COVID-19 and seasonal influenza Pulmonology. 2018;24(4):260–2. doi:10.1016/j.pulmoe.2018.05.004.
among patients presenting to primary care physicians in EU/EEA” 6. Kissling E, Pozo F, Martínez-Baz I, Buda S, Vilcu AM, Domegan L,
(Contract ECD.12850 Lot5 (Primary Care)), funded by the European Mazagatos C, Dijkstra F, Latorre-Margalef N, Kurečić Filipović S,
Centre for Disease Prevention and Control through a service contract et al. Influenza vaccine effectiveness against influenza a subtypes in
with Epiconcept “Vaccine Effectiveness, Burden and Impact Studies Europe: results from the 2021–2022 I-MOVE primary care multi­
(VEBIS) of COVID-19 and Influenza” Contract [ECDC/2021/019]. centre study. Influenza Other Respi Viruses [Internet]. 2023;17.
https://pubmed.ncbi.nlm.nih.gov/36702797/.
7. McLean HQ, Petrie JG, Hanson KE, Meece JK, Rolfes MA,
Sylvester GC, Neumann G, Kawaoka Y, Belongia EA. Interim
ORCID estimates of 2022–23 seasonal influenza vaccine effectiveness —
Wisconsin, October 2022–February 2023. Morb Mortal Wkly Rep
Irina Kislaya http://orcid.org/0000-0001-5772-2416
[Internet]. 2023;72:201–5. doi:10.15585/mmwr.mm7208a1.
Ana Rita Torres http://orcid.org/0000-0003-0486-647X
8. Skowronski DM, Chuang ES, Sabaiduc S, Kaweski SE, Kim S,
Ausenda Machado http://orcid.org/0000-0002-1849-1499
Dickinson JA, Olsha R, Gubbay JB, Zelyas N, Charest H, et al.
Raquel Guiomar http://orcid.org/0000-0002-4563-6315
Vaccine effectiveness estimates from an early-season influenza A
Ana Paula Rodrigues http://orcid.org/0000-0003-2264-4723
(H3N2) epidemic, including unique genetic diversity with reas­
sortment, Canada, 2022/23. Eurosurveillance [Internet].
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