Review

The Association between Influenza Vaccination and COVID-19

and Its Outcomes: A Systematic Review and Meta-Analysis of
Observational Studies
Ruitong Wang 1 , Min Liu 1 and Jue Liu 1,2,3, *

1 Department of Epidemiology and Biostatistics, School of Public Health, Peking University,

Beijing 100191, China; [email protected] (R.W.); [email protected] (M.L.)
2 Institute for Global Health and Development, Peking University, Beijing 100191, China
3 Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China,
Beijing 100083, China
* Correspondence: [email protected]

Abstract: Influenza could circulate in parallel with COVID-19. In the context of COVID-19, some
studies observed inverse associations between influenza vaccination and SARS-CoV-2 infection and
clinical outcomes, while others did not. We conducted a meta-analysis to assess the association
between influenza vaccination and SARS-CoV-2 infection and clinical outcomes, aiming to provide
evidence for COVID-19 prevention and vaccination promotion. We searched four databases from
inception to 10 March, 2021. Random effects and fixed effects models were used to pool odds
ratios (ORs) and adjusted estimates with 95% confidence intervals (CIs). We used funnel plots to
evaluate the publication bias, I2 statistics to evaluate the heterogeneity, and conducted subgroup





 analyses. Sixteen observational studies involving 290,327 participants were included. Influenza
Citation: Wang, R.; Liu, M.; Liu, J.
vaccination was associated with a lower risk of SARS-CoV-2 infection (pooled adjusted OR: 0.86,
The Association between Influenza 95%CI: 0.81–0.91), while not significantly associated with adverse outcomes (intensive care: adjusted
Vaccination and COVID-19 and Its OR 0.63, 95%CI: 0.22–1.81; hospitalization: adjusted OR 0.74, 95%CI: 0.51–1.06; mortality: adjusted
Outcomes: A Systematic Review and OR 0.89, 95%CI: 0.73–1.09). Our findings suggest that influenza vaccination is associated with a lower
Meta-Analysis of Observational Studies. risk of SARS-CoV-2 infection. It is crucial for policy makers to implement strategies on influenza
Vaccines 2021, 9, 529. https:// vaccination, for it may also have benefits for COVID-19 prevention.
doi.org/10.3390/vaccines9050529

Keywords: influenza vaccination; COVID-19; infection; outcome; meta-analysis

Academic Editor:
Luis Martinez-Sobrido

Received: 17 April 2021

1. Introduction
Accepted: 17 May 2021
Published: 20 May 2021
The coronavirus disease (COVID-19) is an acute respiratory infectious disease that
was declared a global public health emergency by the World Health Organization (WHO)
Publisher’s Note: MDPI stays neutral
in January 2020 [1]. The global pandemic has hitherto caused 119 million cases of infection
with regard to jurisdictional claims in
and 2 million cases of death [1], and imposed tremendous burden on global health and
published maps and institutional affil- worldwide economics. Thus, effective cures and vaccines are imperatively needed to
iations. curtail the pandemic and decrease mortality. Seasonal influenza occurs from fall to spring
annually, characterized by the circulation of influenza A or B virus [2]. Influenza and its
complications could lead to increased worldwide mortality and morbidity, which remain a
public health threat.
Copyright: © 2021 by the authors.
Due to the seasonality of influenza outbreaks and the continuous prevalence of COVID-
Licensee MDPI, Basel, Switzerland.
19, influenza could circulate in parallel with COVID-19, which largely increases the po-
This article is an open access article
tential risk of co-infection. Though little is known about the epidemiology and clinical
distributed under the terms and outcomes of co-infection, extant literature has found that the co-infection with influenza
conditions of the Creative Commons A virus enhances the infectivity of COVID-19 in a broad range of cell types [3], whereas
Attribution (CC BY) license (https:// co-infected patients seem to present similar clinical symptoms and radiological images
creativecommons.org/licenses/by/ compared with patients infected with COVID-19 alone [4,5]. In the context of the COVID-
4.0/). 19 pandemic, the dual infection of influenza and COVID-19 could bring extra burden

Vaccines 2021, 9, 529. https://doi.org/10.3390/vaccines9050529 https://www.mdpi.com/journal/vaccines

Vaccines 2021, 9, 529 2 of 17

to health care services by utilizing limited medical resources, increasing the difficulty of
treatment and the uncertainty of prognosis. Annual influenza vaccination has long been
recommended by WHO to prevent influenza, especially to the high-risk populations with
disproportionate infection and severe complications, such as older adults (aged > 65 years)
and pregnant women [6]. To date, no highly effective pharmaceutical treatment is available
against COVID-19 [7]. Though COVID-19 vaccines remain the most effective long-term
solution to combat COVID-19 pandemic [8], the overall effectiveness and safety of the
licensed COVID-19 vaccines remain to be fully evaluated based on real-world evidence.
According to a previous study by Wolff [9], which investigated influenza vaccine-
related virus interference by specific respiratory viruses (e.g., coronavirus, human bo-
cavirus, and adenovirus), there was an increased odd of coronavirus in individuals receiv-
ing influenza vaccination. This finding raised much concerns of the possible relationship
between influenza vaccination and coronavirus, especially in the COVID-19 pandemic. In
addition, as COVID-19 and influenza are both respiratory infectious diseases caused by
enveloped RNA viruses that share similarities in transmission routes and clinical character-
istics [10], more and more researchers began to seek for relationships between SARS-CoV-2
infection and influenza immunity. Based on the assumptions, Del Riccio et al. [11] con-
ducted a systematic review and found that there was overall no evidence to suggest a
negative impact of influenza vaccination on SARS-CoV-2 related infections, illness, or
deaths, while some of the included studies even reported significantly inverse associations.
Though some of the recent studies have found that influenza vaccine uptake was negatively
associated with COVID-19 incidence [12,13], severity [13,14], and mortality [13,15], others
showed no evidence of such associations [16–18]. Therefore, a systematic review and
meta-analysis of the association between influenza vaccination and SARS-CoV-2 infection
and its outcomes is needed to provide conclusive evidence.
In the dual epidemics of COVID-19 and influenza, influenza vaccination has a more
significant implication than ever for preventing both influenza and COVID-19. It is es-
pecially of great necessity for vulnerable populations to receive influenza vaccination.
Given the limited data of COVID-19 vaccine effectiveness among vulnerable groups, as
well as the necessity of influenza vaccination in the context of COVID-19, and the lack
of conclusive evidence of influenza vaccination’s effect on SARS-CoV-2 infection and its
clinical outcomes, there is a need to systematically assess the potential association between
influenza vaccination and COVID-19. In this regard, we conducted a systematic review
and meta-analysis to assess the overall association between influenza vaccination and
SARS-CoV-2 infection and clinical outcomes, aiming to provide evidence for public health
decision makers to develop COVID-19 preventive measures and provide implications for
vaccination promotion.

2. Materials and Methods

2.1. Data Sources and Search Strategy
We searched PubMed, Embase, Web of Science, and Cochrane Library for eligible
studies published from June 1971 to 10 March, 2021 using the following search terms: (‘flu’
OR ‘influenza’) AND (‘COVID-19’ OR ‘SARS-CoV-2’ OR ‘coronavirus’) AND (‘vaccination’
OR ‘vaccine’). We used EndNote 20 software to manage records, exclude duplicates, and
screen abstracts and titles. This study was conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and
the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We
prospectively submitted the systematic review protocol for registration on PROSPERO
(registration ID: CRD42021244442).

2.2. Data Sources and Search Strategy

We basically included observational studies that examined the association between
influenza vaccination and SARS-CoV-2 infection or reported the association between
influenza vaccination and clinical outcomes among SARS-CoV-2 infected populations.
Vaccines 2021, 9, 529 3 of 17

The following studies were excluded: (1) irrelevant to the subject of the meta-analysis,
such as studies that did not use influenza vaccination as the exposure or did not report
the outcomes; (2) insufficient data to calculate the odds ratio (OR) or select the adjusted
estimates (aRR or aOR) on the association between influenza vaccination and SARS-CoV-2
infection and outcomes; (3) duplicate studies or overlapping participants; (4) reviews,
editorials, conference papers, case reports or animal experiments; (5) studies that did not
mention the identification of COVID-19. For example, the confirmed diagnosis of COVID-
19 via reverse-transcription polymerase chain reaction (rt-PCR) test, serologic test, or other
means were not mentioned in the text; and (6) studies that did not clarify the ascertainment
of influenza vaccination (health system record/self-report).
Studies were identified by two investigators (R.W. and J.L.) independently following
the criteria above, while discrepancies were resolved with a third investigator (M.L.).

2.3. Quality Assessment

We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale
for cohort studies and case-control studies [19], while the methodological quality of cross-
sectional studies was assessed using the checklist recommended by Agency for Healthcare
Research and Quality (AHRQ) [20]. Cohort studies and case-control studies were classified
as having low (≥7 stars), moderate (5–6 stars), and high (≤4 stars) risk of bias with an
overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the
AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and
summarized scores across items to generate an overall quality score that ranged from 0 to
11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and
0–3, respectively. Two investigators (R.W. and J.L.) independently assessed study quality,
with disagreements resolved by a third investigator (M.L.).

2.4. Data Extraction

The primary outcome was the association between influenza vaccination and SARS-
CoV-2 infection, and the secondary outcome was the association between influenza vacci-
nation and clinical outcomes of SARS-CoV-2 infection. The following data were extracted
independently from the selected studies: (1) basic information of the studies, including first
author, publication year, variables adjusted in the analysis and study design; (2) character-
istics of the study population, including sample sizes, age groups, or regions; (3) seasons
for influenza vaccination of the exposed group; (4) primary outcomes: the number of
SARS-CoV-2 infected and non-infected people and by vaccination status (vaccinated or un-
vaccinated); (5) secondary outcomes: the number of influenza vaccinated and unvaccinated
people and by clinical outcomes of SARS-CoV-2 infection (e.g., hospitalization, mortality,
and intensive care); and (6) adjusted estimates (aRR or aOR) with 95% CI that were relevant
to the primary or secondary outcomes. If a study reported the crude estimates or adjusted
estimates of different influenza seasons, only the estimates of the most recent influenza
season were included.

2.5. Data Synthesis and Statistical Analysis

We performed a meta-analysis to pool data from observational studies and assessed
the overall associations between influenza vaccination and COVID-19 by clinical outcomes
(infected vs. uninfected, hospitalization vs. non-hospitalization, death vs. alive, intensive
care vs. non-intensive care). Random effects and fixed effects models were used to pool the
crude ORs and adjusted ORs across studies separately. The pooled estimates were deemed
significant when the according 95%CIs did not pass through zero and the p value was less
than 0.05.
We conducted subgroup analyses to investigate the possible sources of heterogeneity
by using study designs, sample sizes, and regions as grouping variables. We used the Q
test to conduct subgroup comparisons and variables were considered significant between
subgroups if the subgroup difference p value was less than 0.05. Sensitivity analyses were
Vaccines 2021, 9, 529 4 of 17

performed by omitting one study at a time to assess studies with notable impact and
examine the robustness of the overall effect. Funnel plots and Egger’s tests were used to
assess publication bias. We analyzed data using Stata version 16.0 and R version 4.0.2.

3. Results
3.1. Study Selection and Study Characteristics
A total of 2895 records were retrieved from the four databases and 1467 duplicates
were excluded. After screening titles and abstracts, we excluded 1387 reviews, conference
papers, animal experiments, case reports, and other studies irrelevant to the subject or pub-
lished before December 2019. Among the 41 articles assessed based on full texts, 25 articles
were excluded for lacking specific data or did not meet the inclusion criteria. A total
of 16 studies were finally included in the review (12 studies on the association between
influenza vaccination and SARS-CoV-2 infection [16,18,21–30], 6 on the association be-
tween influenza vaccination and COVID-19 clinical outcomes [10,17,22,26,31,32], 2 studies
containing data on both the associations [22,26]. Nine of the 12 studies on the association
between influenza vaccination and SARS-CoV-2 infection contained adjusted estimates.
One [21] of the 16 studies has moderate risk of bias, while the others have low risk of bias.
The primary outcome (the association between influenza vaccination and SARS-CoV-2
infection) comprised a total of 208,132 people (72,820 vaccinated and 135,112 unvaccinated).
The secondary outcome (the association between influenza vaccination and clinical out-
comes of SARS-CoV-2 infection) comprised a total of 82,684 COVID-19 patients and was
assessed by different outcomes (mortality, intensive care, and hospitalization). The study
selection procedure is shown in Figure 1. The baseline characteristics of the included
studies are listed in Table 1 (primary outcome) and Table 2 (secondary outcome). The
adjusted variables of the included studies were basically age, sex, comorbidities, prescribed
medications and smoking status, but were not the same across studies (see Tables 1 and 2).
Vaccines 2021, 9, 529 5 of 17

Table 1. Baseline characteristics of the 12 included studies that assessed the association between influenza vaccination and SARS-CoV-2 infection.

Quality Score
Infected Adjusted
Vaccination Identification Sample Infected and Risk of
Study Study Design Country (n)/Unvaccinated Estimate Adjusted Factors
Season of COVID-19 Size (n)/Vaccinated(n) Bias
(n) (95%CI)
Assessment
Massoudi et al., Case-control pulmonologist-
2019–2020 Iran 261 3/90 77/171 - 6(moderate) -
(2021) [21] study confirmed
Study site, time, age,
Kissling et al., Case-control
2019–2020 rt-PCR Europe a 1701 68/429 157/1272 0.93 (0.66–1.32) 8 (low) sex, and chronic
(2021) [18] study
condition
Age, sex, Charlson
Ragni et al., (2020) Case-control
2019–2020 rt-PCR Italy 17,608 1676/5427 3209/12,181 0.89 (0.80–0.99) 9 (low) index, and time of the
[22] study
swab test
Age, sex, and an
interaction term
Belingheri et al., Cross-sectional
2019–2020 rt-PCR Italy 3520 28/817 100/2703 0.41 (0.07–2.39) 7 (low) between age and the
(2020) [23] study
vaccination intake in
2019/3020
Vila-Córcoles Retrospective Age, sex, and
2019–2020 rt-PCR Spain 1547 189/705 160/842 0.63 (0.43–0.92) b 8 (low)
et al., (2020) [24] cohort study comorbidities
Pawlowski et al., Retrospective
2019–2020 rt-PCR America 25,582 442/12,791 521/12,791 - 8 (low) -
(2021) [26] cohort study
Jehi et al., (2020) Prospective
-c rt-PCR America 11,672 384/6324 434/5348 - 7 (low) -
[27] cohort study
Age, sex,
Vila-Córcoles Retrospective
2019–2020 rt-PCR Spain 78,883 205/22,606 175/56,277 1.02 (0.79–1.32) b 7 (low) comorbidities, and
et al., (2020) d [25] cohort study
medications use.
Age groups, sex, major
chronic conditions,
Martínez-Baz Prospective
2019–2020 rt-PCR Spain 10,714 155/3677 248/7037 1.03 (0.83–1.27) 7 (low) profession, and any ILI
et al., (2020) e [16] cohort study
diagnosis in the
previous five years
Vaccines 2021, 9, 529 6 of 17

Table 1. Cont.

Quality Score
Infected Adjusted
Vaccination Identification Sample Infected and Risk of
Study Study Design Country (n)/Unvaccinated Estimate Adjusted Factors
Season of COVID-19 Size (n)/Vaccinated(n) Bias
(n) (95%CI)
Assessment
Age, sex, education,
area of residence,
Noale et al., Cross-sectional
2019–2020 rt-PCR Italy 6680 562/2246 1114/4434 0.89 (0.78–1.01) 8 (low) self-reported
(2020) [28] study
comorbidities, and
smoking status
Age, ethnic, smoking
Green et al., Cross-sectional status, socioeconomic
2019–2020 rt-PCR Israel 22,563 244/4711 1580/17,852 0.79 (0.67–0.98) 9 (low)
(2020) [29] study status, and
comorbidities
Ethnicity, race, sex,
Conlon et al., Retrospective age, BMI, Elixhauser
2019–2020 rt-PCR America 27,201 525/12,997 693/14,204 0.76 (0.68–0.86) 8 (low)
(2021) [30] cohort study score, smoking status,
and comorbidities
a:France, Netherlands, Sweden b : aRR, the others are all aOR. c : Not specifically defined, but records can be retrieved in the health care system. d : the uninfected populations contain those who had suspected
infection but were not tested. e : the uninfected populations contain those who were not tested with no suspected infection. rt—PCR, reverse transcription-polymerase chain reaction.

Table 2. Baseline characteristics of the six included studies that assessed the association between influenza vaccination and SARS-CoV-2 outcomes.

Quality Score
Events Adjusted
Vaccination Identification Sample Events and Risk of
Study Study Design Country (n)/Unvaccinated Estimate Adjusted Factors
Season of COVID-19 Size (n)/Vaccinated(n) Bias
(n) (95%CI)
Assessment
Intensive Care
Pawlowski et al., Retrospective
2019–2020 rt-PCR America 959 15/441 16/518 - 8 (low) -
(2020) [26] cohort study
de la Cruz Conty et al., Prospective
-b rt-PCR Spain 1150 7/438 15/712 - 7 (low) -
(2021) a [17] cohort study
Age, sex, race,
Retrospective b Clinical educational level,
Fink et al., (2020) [10] - Brazil 53,752 - - 0.93 (0.87–0.99) 7 (low)
cohort study diagnosisc treatment facility, and
comorbidities
Age, sex
Retrospective race/ethnicity,
Yang et al., (2021) [32] 2019–2020 rt-PCR America 2005 3/214 133/1791 0.30 (0.07–0.85) 8 (low)
cohort study hypertension, and
comorbidities
Vaccines 2021, 9, 529 7 of 17

Table 2. Cont.

Quality Score
Events Adjusted
Vaccination Identification Sample Events and Risk of
Study Study Design Country (n)/Unvaccinated Estimate Adjusted Factors
Season of COVID-19 Size (n)/Vaccinated(n) Bias
(n) (95%CI)
Assessment
Hospitalization
Pawlowski et al., Retrospective
2019–2020 rt-PCR America 959 74/441 78/518 - 8 (low) -
(2020) [26] cohort study
Age, sex
Retrospective race/ethnicity,
Yang et al., (2021) [32] 2019–2020 rt-PCR America 2005 43/214 747/1791 0.41 (0.28–0.60) 8 (low)
cohort study hypertension, and
comorbidities
Age, sex, Charlson
retrospective
Ragni et al., (2020) [22] 2019–2020 rt-PCR Italy 17,608 - - 0.84 (0.83–1.29) d 7 (low) index, and time of the
cohort study
swab test
Age, sex, BMI,
socioeconomic status,
smoking status, frailty
Wilcox et al., (2021) e retrospective
2019–2020 rt-PCR England 6921 1166/2613 1584/4308 0.85 (0.75–0.97) 8 (low) score, comorbidities,
[31] cohort study
and the number of
prescribed
medications
Mortality
Age, sex, race,
Retrospective b Clinical educational level,
Fink et al., (2020) [10] - Brazil 53,752 - - 0.84 (0.77–0.91) 7 (low)
cohort study diagnosis c treatment facility, and
comorbidities
Age, sex, Charlson
retrospective
Ragni et al., (2020) [22] 2019–2020 rt-PCR Italy 17,608 - - 1.14 (0.95–1.37) d 7 (low) index, and time of the
cohort study
swab test
Age, sex, BMI,
socioeconomic status,
smoking status, frailty
Wilcox et al., (2021) retrospective
2019–2020 rt-PCR England 6921 372/2613 553/4308 0.76 (0.64–0.90) 8 (low) score, comorbidities,
[31] cohort study
and the number of
prescribed
medications
a: Intensive care unit admission/mechanical ventilation/septic shock. b : Not specifically defined but records can be retrieved in the health care system. c : 79.8% of these patients had a documented positive
rt-PCR test. d : aRR, the others are all aOR. e : Hospitalization or all-cause mortality. rt—PCR, reverse transcription-polymerase chain reaction.
Vaccines 2021, 9, x FOR PEER REVIEW 5 of 17

Vaccines 2021, 9, 529 8 of 17

Figure
Figure 1.
1. PRISMA
PRISMA flow
flow diagram
diagram of
of the
the study
study selection
selection procedure.
procedure.

3.2. of
Table 1. Baseline characteristics ThetheAssociation
12 includedbetween Influenza
studies that Vaccination
assessed and COVID-19
the association and Its Outcomes
between influenza vaccination and
SARS-CoV-2 infection. The association between influenza vaccination and SARS-CoV-2 infection is presented
in Figure 2, Table 3 and Supplementary Table S1. Influenza vaccination was shown to be
Quality
associated with a lower risk of SARS-CoV-2 infection
Infected in both
Infected modelsScore
Adjusted (fixed effects model:
and
Study De- Vaccination
pooledIdentification
adjusted OR: 0.86, Sample
95%CI: 0.81–0.91; Adjusted
Study Country (n)/Vac- (n)/Unvac- Estimate Risk of adjusted OR:
random effects model: pooled
sign Season of COVID-19 Size Factors
0.86, 95%CI: 0.79–0.94). cinated(n) cinated (n) (95%CI) Bias As-
sessment
pul-
Massoudi et Case-con- 6(moder-
2019–2020 monologist- Iran 261 3/90 77/171 - -
al., (2021) [21] trol study ate)
confirmed
Study site,
Kissling et al., Case-con- 0.93 (0.66–
2019–2020 rt-PCR Europe a 1701 68/429 157/1272 8 (low) time, age,
(2021) [18] trol study 1.32)
sex, and
s 2021, 9, xVaccines
FOR PEER2021, 9, 529
REVIEW 9 of 17 9 of 17

Figure 2. Forest plots for the association between influenza vaccination and SARS-CoV-2 infection:
Figure 2. Forest plots forOR
(A) adjusted theby
association between
fixed effects modelinfluenza vaccination
(B) adjusted and SARS-CoV-2
OR by random infection: (A) adjusted OR by
effects model.
fixed effects model (B) adjusted OR by random effects model.
Table 3. Summary of the overall association between influenza vaccination and SARS-CoV-2 infection and clinical outcomes.

Adjusted Estimates a (95%CI)

Outcomes Number of Studies I2 Value (%) p Value
Fixed Effects Model Random Effects Model
RS-CoV-2 infection 9 41.1 0.09 0.86 (0.81–0.91) 0.86 (0.79–0.94)
Intensive care 2 68.2 0.08 0.93 (0.87–0.99) 0.63 (0.22–1.81)
Hospitalization 3 87.6 <0.01 0.84 (0.75–0.93) 0.74 (0.51–1.06)
Mortality 3 82.5 <0.01 0.86 (0.81–0.93) 0.89 (0.73–1.09)
a: Adjusted OR or adjusted RR.
Vaccines 2021, 9, 529 10 of 17

Table 3. Summary of the overall association between influenza vaccination and SARS-CoV-2 infection and clinical outcomes.

Adjusted Estimates a (95%CI)

Outcomes Number of Studies I2 Value (%) p Value
Fixed Effects Model Random Effects Model
SARS-CoV-2 infection 9 41.1 0.09 0.86 (0.81–0.91) 0.86 (0.79–0.94)
Intensive care 2 68.2 0.08 0.93 (0.87–0.99) 0.63 (0.22–1.81)
Hospitalization 3 87.6 <0.01 0.84 (0.75–0.93) 0.74 (0.51–1.06)
Mortality 3 82.5 <0.01 0.86 (0.81–0.93) 0.89 (0.73–1.09)
a: Adjusted OR or adjusted RR.

The association between influenza vaccination and COVID-19 outcomes are presented
in Table 3 and Supplementary Table S1. The association between influenza vaccination
and intensive care (adjusted OR: 0.63, 95%CI: 0.22–1.81), hospitalization (adjusted OR: 0.74,
95%CI: 0.51–1.06), or mortality (adjusted OR: 0.89, 95%CI: 0.73–1.09) among COVID-19 pa-
tients was not statistically significant by random effects model, while results by fixed effects
model was somehow significant. This may be due to the substantial heterogeneity between
the small number of studies (2–3 studies) and participants involved in each outcome.

3.3. Subgroup Analysis

Given the heterogeneity among the outcomes of the association between influenza
vaccination and SARS-CoV-2 infection (Figure 2, Table 3), we conducted subgroup analyses
by sample sizes, regions, and study designs. The results of subgroup analyses are presented
in Figure 3, Supplementary Figure S1, Table 4 and Supplementary Table S2. There was no
significant evidence of association stratified by sample sizes or study designs (all p > 0.05).
However, there was substantial heterogeneity between the adjusted estimates of studies in
Europe (0.90, 95%CI: 0.84–0.97), America (0.76, 95%CI: 0.68–0.85), and Asia (0.79, 95%CI:
0.65–0.96, p = 0.03).
Owing to the paucity of the included studies on the association between influenza
vaccination and any of the COVID-19 outcomes (mortality, hospitalization, and intensive
care), planned subgroup analyses were not able to be performed.

Table 4. Subgroup analyses of the association between influenza vaccination and SARS-CoV-2 infection.

Random Effects Model Fixed Effects Model

Grouping
No. of Studies Adjusted Estimate Adjusted Estimate
Variables I2 Value (%) p Value I2 Value (%) p Value
(95%CI) (95%CI)
Region 9 0.04 a 0.03 a
Europe 7 0.91 (0.84–0.98) 10.4 <0.01 b 0.90 (0.84–0.97) 10.4 <0.01 b
Asia 1 0.79 (0.65–0.96) - - 0.79 (0.65–0.96) - -
America 1 0.76 (0.68–0.85) - - 0.76 (0.68–0.85) - -
Sample size 9 0.34 a 0.06 a
Sample size
6 0.89 (0.82–0.97) 13.3 0.33 b 0.89 (0.83–0.96) 13.3 0.33 b
<20,000
Sample size
3 0.82 (0.71–0.96) 52.2 0.12 b 0.80 (0.73–0.88) 52.2 0.12 b
≥20,000
Study design 9 0.83 a 0.55 a
Case-control
2 0.89 (0.81–0.99) 0.0 0.81 b 0.89 (0.81–0.99) 0.0 0.81 b
study
Cross-sectional
3 0.85 (0.77–0.95) 0.0 0.43 b 0.85 (0.77–0.95) 0.0 0.43 b
study
Cohort study 4 0.86 (0.70–1.05) 71.7 0.01 b 0.83 (0.75–0.91) 71.7 0.01 b
a: p value for subgroup difference. b : p value for heterogeneity.
Vaccines 2021,
Vaccines 9, 529
2021, 9, x FOR PEER REVIEW 11 17
11 of of 17

Figure 3. Forest plots for subgroup analysis on the association between influenza vaccination and SARS-CoV-2 infection
Figure 3. Forest plots for subgroup analysis on the association between influenza vaccination and SARS-CoV-2 infection by
by fixed effects model: (A) stratified by region (B) stratified by sample size (C) stratified by study design.
fixed effects model: (A) stratified by region (B) stratified by sample size (C) stratified by study design.
3.4. Publication Bias and Sensitivity Analysis
3.4. Publication Bias and Sensitivity Analysis
In the sensitivity analyses regarding the association between influenza vaccination
andIn the sensitivity
SARS-CoV-2 analyses
infection, theregarding the association
pooled estimates betweenwhen
were consistent influenza vaccination
any one of the
and SARS-CoV-2 infection, the pooled estimates were consistent
studies was omitted, which demonstrated the robustness of the results. Sensitivitywhen any oneanal-
of the
studies
yses on wastheomitted, whichbetween
association demonstrated the vaccination
influenza robustness ofandthe clinical
results. outcomes
Sensitivityamong
analyses
on the association
COVID-19 between
patients were not influenza vaccination
carried out owing to and clinical outcomes
the sparseness among COVID-19
of the included studies.
patients
Thewere not carried
summary of the out owing tobias
publication theare
sparseness
presentedofinthe included
Table studies.
5 and Figure 4. Both fun-
The summary
nel plots and Egger’sof the
testspublication
showed nobias are presented
evidence in Table
of publication bias5 for
andthe
Figure 4. Both
pooled funnel
estimates
plots and Egger’s tests showed no evidence of publication bias for the
and adjusted estimates of the association between influenza vaccination and SARS-CoV- pooled estimates
and adjusted(all
2 infection estimates
p > 0.05).ofNeither
the association
evidencebetween influenza
of publication bias vaccination and SARS-CoV-2
for the association between
infection (all p > 0.05). Neither evidence of publication bias for the association
influenza vaccination and COVID-19 related hospitalization or COVID-19-related mortal- between
influenza vaccination
ity were observed (alland
p > COVID-19
0.05). related hospitalization or COVID-19-related mortality
were observed (all p > 0.05).
Vaccines 2021, 9, 529 12 of 17

Table 5. Summary of publication bias on the association between influenza vaccination and SARS-
CoV-2 infection and clinical outcomes.

Outcomes t Value p Value

SARS-CoV-2 infection −0.19 0.85
Mortality 0.46 0.73
Vaccines 2021, 9, x FOR PEER REVIEW Hospitalization −0.87 0.55 12 of 17
Results from adjusted OR.

Figure 4. Funnel plots for the associations between influenza vaccination and SARS-CoV-2 infection and clinical outcomes:
Figure 4. Funnel plots for the associations between influenza vaccination and SARS-CoV-2 infection and clinical outcomes:
(A) adjusted OR of SARS-CoV-2 infection (B) mortality (C) hospitalization.
(A) adjusted OR of SARS-CoV-2 infection (B) mortality (C) hospitalization.
Table 5. Summary of publication bias on the association between influenza vaccination and SARS-
4.CoV-2
Discussion
infection and clinical outcomes.
To our best knowledge, this is the first meta-analysis that systematically assessed
the association Outcomes
between influenza vaccination t Value p Value
and SARS-CoV-2 infection, and the associ-
SARS-CoV-2 infection −0.19 0.85
ation between influenza vaccination and clinical outcomes of SARS-CoV-2 infection. We
ultimately includedMortality
a total of 16 studies (12 on 0.46
SARS-CoV-2 infection and 0.73 six on clinical
Hospitalization −0.87 0.55
outcomes of SARS-CoV-2 infection, two on both) that had evaluated the associations. We
Results from
observed adjusted OR.
a significant association between influenza vaccination and SARS-CoV-2 infection
by pooling the adjusted estimates, while no evidence of the association was found between
4. Discussion
influenza vaccination and any of the clinical outcomes (hospitalization, mortality, and
To our
intensive best
care) knowledge,
among this isinfected
COVID-19 the firstpatients.
meta-analysis that systematically assessed the
association between influenza vaccination
In the era of the COVID-19 pandemic, simply and SARS-CoV-2 infection,
having licensed and theisassociation
vaccines not enough
between
to achieveinfluenza vaccination
global control and clinical
of COVID-19. outcomes
Vaccines alsoofneed
SARS-CoV-2 infection.
to be globally We ulti-
allocated and
mately included a total of 16 studies (12 on SARS-CoV-2 infection and six on clinical out-
comes of SARS-CoV-2 infection, two on both) that had evaluated the associations. We ob-
served a significant association between influenza vaccination and SARS-CoV-2 infection
by pooling the adjusted estimates, while no evidence of the association was found be-
tween influenza vaccination and any of the clinical outcomes (hospitalization, mortality,
and intensive care) among COVID-19 infected patients.
Vaccines 2021, 9, 529 13 of 17

widely deployed [33]. Currently, only 4.3% of the global population have received at least
one dose of a COVID-19 vaccine [34]. Vulnerable groups, such as the elderly and pregnant
women, are usually not specifically included in COVID-19 clinical trials. Meanwhile,
considerable mutation of SARS-CoV-2 has occurred since its initial emergence, which may
have impact on the effectiveness of current vaccines and should be considered in vaccine
design and development [35].
Influenza vaccination is regarded as the most effective measure to prevent influenza
and influenza-related complications, especially for high-risk populations [36]. Previous
studies suggested that older adults and pregnant women with influenza vaccination had a
significantly lower risk of getting laboratory-confirmed influenza (older adults: risk ratio
(RR) 0.76, 95%CI: 0.65–0.90; pregnant women: RR 0.3, 95% CI: 0.26–0.35) [37,38], which
demonstrated relatively high effectiveness of influenza vaccines and highlighted the neces-
sity of influenza vaccination. Restivo et al. [39] reported that influenza vaccine effectiveness
was 39% (95%CI: 32–46%) for hospital visits and 57% (95%CI: 30–74%) for hospitalization
among children, and the rate was 25% (95%CI: 6–40%) for visits and 14% (95%CI: 7–21%)
for hospitalization among older adults. Cheng et al. [40] conducted a meta-analysis that
included 29 studies and found that influenza vaccination was associated with a lower
risk of overall adversary respiratory outcomes (including asthma, chronic obstructive pul-
monary disease, unspecific respiratory diseases, respiratory failure, respiratory infections,
pneumonia, and respiratory mortality) in the group aged over 65, from which significant
associations were detected between influenza vaccination and pneumonia (aRR 0.79, 95%
CI: 0.65−0.95) and respiratory mortality (aRR 0.79, 95 % CI: 0.67−0.92). These results
showed that influenza vaccination was effective at protecting vulnerable populations from
influenza and its complications.
Due to the constant slight changes that influenza viruses undergo each season, in-
fluenza vaccines are required to be modified annually to maintain their effectiveness.
Though influenza vaccination has been recommended by the WHO and other global orga-
nizations, annual influenza vaccine coverage remains to be relatively low in vulnerable
populations. The overall influenza vaccination uptake rate among subjects with high-
risk chronic conditions in Spain in 2017 was only 40.1% and decreased significantly from
2014 [41]. Though the rate among American children aged from 6 months to 17 years
old increased from 16.70% during 2004/2005 to 49.43% during 2015/2016, it was still far
below the U.S. Healthy People 2020 target of 70% annual influenza vaccination cover-
age among children [42]. In France, influenza vaccine coverage among pregnant women
was only 7.4% in 2015/2016 season [43]. Effective interventions and tailored measures
should be conducted to promote influenza vaccination and reduce vaccine hesitancy among
high-risk populations.
Apart from playing an important role in influenza prevention, seasonal influenza
vaccination is considered to have additional value in the strained period of COVID-19
pandemic. Influenza vaccination can reduce influenza-related hospital visits, thereby
largely reducing the potential risk of respiratory infectious diseases, such as COVID-19,
alleviating the burden of health care systems and saving medical resources for the treatment
of other severe diseases [44]. It is also believed that being protected against influenza by
vaccination enhances the accuracy of COVID-19 diagnosis and the specificity of COVID-19
surveillance [45].
In our study, we found that the influenza vaccination was associated with a lower risk
of SARS-CoV-2 infection. One possible explanation was that those who received influenza
vaccinations in the past seasons tended to pay more attention to their health status, thus
they might have been more compliant with COVID-19 prevention measures, such as social
distancing and wearing masks, which reduced their potential risk of infection. In addition,
influenza vaccination could reduce the risk of influenza, which reduces the possibility of
hospital visits and the risk of SARS-CoV-2 infection in high-risk areas, such as hospitals.
Another possible theory that could explain influenza vaccine’s protective effect against
COVID-19 is the trained immunity process. Influenza vaccines may induce non-specific
Vaccines 2021, 9, 529 14 of 17

activation of innate immune cells (e.g., natural killer cells) by increasing proinflammatory
cytokine production, thereby triggering the non-specific protective effects against the
diseases caused by heterologous viruses [46,47]. Such a mechanism has been demonstrated
in Bacillus Calmette–Guérin (BCG) vaccine’s protective effective against malaria [48].
Accelerated natural killer cells and monocyte activation that correlated with reduced
parasitemia was observed in the BCG vaccinated volunteers, which was consistent with
the possibility of trained immunity. Likewise, influenza vaccination might be associated
with a lower risk of COVID-19 via trained immunity. The underlying mechanism of the
potential association between influenza vaccination and SARS-CoV-2 infection awaits
further exploration.
Although we observed no evidence of a significant association between influenza
vaccination and the lower risk of clinical outcomes among COVID-19 patients, Hui et al. [49]
found that exposure of influenza A virus may upregulate the angiotensin-converting
enzyme 2 (ACE2) receptors in alveolar epithelial cells, which facilitates SARS-CoV-2 virus
to enter into alveolar epithelial cells and worsen clinical outcomes of SARS-CoV-2 infection.
However, such effect was not observed in human macrophages. Bai et al. [3] found
that influenza A virus promotes the infectivity of SARS-CoV-2 virus. The co-infection of
influenza A virus and SARS-CoV-2 virus in mice resulted in increased SARS-CoV-2 viral
load and more severe lung damage. Therefore, influenza vaccination may have a positive
effect on better clinical outcomes of SARS-CoV-2 infection. More conclusive evidence is
needed in the future.
In the subgroup analysis, statistics indicated that regions might be the potential
sources of heterogeneity for the association between influenza vaccination and SARS-CoV-
2 infection. The regional difference of the association between influenza vaccination and
SARS-CoV-2 infection might result from various factors, including the diverse characteris-
tics and immunity of the populations, the difference in the toxicity of SARS-CoV-2 viruses
and dominant strains, and the efforts of COVID-19 prevention and control across regions.
The limitations in this study are listed as follows. First, subgroup analyses and
sensitivity analyses on the association between influenza vaccination and the clinical
outcomes of SARS-CoV-2 infection were not performed due to the limited number of
studies. Similarly, publication bias was not adequately assessed. More relevant studies are
needed to provide more precise pooled estimates. Second, only observational studies were
available and included in our meta-analysis, so that the evidence regarding the intervention
was not as strong as randomized controlled trials [50]. Nonetheless, this meta-analysis was
performed strictly in accordance with the MOOSE guideline. Studies included in this meta-
analysis took certain measures to minimize potential biases in selection and confounders,
and all showed low to moderate risk of biases. Third, the exact influenza vaccination
seasons and the confirmation of COVID-19 patients in some of the included studies were
not specifically defined. Age groups and types of influenza viruses were not able to be
used as grouping variables in subgroup analyses for lack of sufficient feasible studies with
clear definitions and classifications. Additionally, studies included in the meta-analysis
were all conducted before December 2020 when COVID-19 vaccines were not licensed yet.
Some participants may have entered COVID-19 vaccine clinical trials and received vaccines,
but were not reported in the studies, which may have impact on our analysis. However,
the proportion of volunteers in COVID-19 vaccine trials could be very low and had little
effects on our study. Last it was not possible to fully evaluate the possibility of overlapping
participants among the included studies due to limited data. Nonetheless, this is the first
meta-analysis that systematically assessed the association between influenza vaccination
and COVID-19 and its outcomes, which could provide evidence-based medicine basis for
the prevention of COVID-19 and influenza vaccination promotion.

5. Conclusions
This meta-analysis indicates that the influenza vaccination is associated with a lower
risk of SARS-CoV-2 infection, while its association with clinical outcomes (mortality, hospi-
Vaccines 2021, 9, 529 15 of 17

talization, and intensive care) of SARS-CoV-2 infection is not found. In the dual epidemics
of the COVID-19 pandemic and influenza, it is especially crucial for policymakers to imple-
ment strategies aimed at promoting influenza vaccination, and that relevant public health
campaigns and policy initiatives should be put in place to inform people of influenza
vaccination benefits for the prevention and control of COVID-19. More evidence-based
studies are urgently warranted to explore the association between influenza vaccination
and SARS-CoV-2 infection and its outcomes, along with more in-depth research needed to
further explain the underlying mechanisms for the associations.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/vaccines9050529/s1, Table S1: Summary of the overall association between influenza vaccina-
tion and SARS-CoV-2 infection and clinical outcomes by crude OR; Table S2: Subgroup analyses of
the association between influenza vaccination and SARS-CoV-2 infection by crude OR; Figure S1:
Forest plots for subgroup analysis on the association between influenza vaccination and SARS-CoV-2
infection by random effects model: (A) stratified by region (B) stratified by sample size (C) stratified
by study design.
Author Contributions: Conceptualization, R.W. and J.L.; methodology, R.W. and J.L.; software,
R.W.; validation, R.W., J.L. and M.L.; formal analysis, R.W.; data curation, R.W.; writing—original
draft preparation, R.W.; writing—review and editing, R.W., M.L., and J.L.; visualization, R.W.;
supervision, J.L.; funding acquisition, J.L. All authors have read and agreed to the published version
of the manuscript.
Funding: This work was funded by the National Key Research and Development Project of China
[grant numbers 2020YFC0846300, 2019YFC1710301]; the National Science and Technology Key Projects
on Prevention and Treatment of Major infectious disease of China (grant number 2020ZX10001002); and
the National Natural Science Foundation of China (grant numbers 71874003, 71934002, 81703240).
Data Availability Statement: Data are available from the corresponding author by request.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. World Health Organization. Weekly Epidemiological Update on COVID-19. Available online: https://www.who.int/
publications/m/item/weekly-epidemiological-update-on-covid-19 (accessed on 10 April 2021).
2. Nelson, M.I.; Tan, Y.; Ghedin, E.; Wentworth, D.E.; St George, K.; Edelman, L.; Beck, E.T.; Fan, J.; Lam, T.T.-Y.; Kumar, S.; et al.
Phylogeography of the spring and fall waves of the H1N1/09 pandemic influenza virus in the United States. J. Virol. 2011, 85,
828–834. [CrossRef]
3. Bai, L.; Zhao, Y.; Dong, J.; Liang, S.; Guo, M.; Liu, X.; Wang, X.; Huang, Z.; Sun, X.; Zhang, Z.; et al. Coinfection with influenza A
virus enhances SARS-CoV-2 infectivity. Cell. Res. 2021, 31, 395–403. [CrossRef] [PubMed]
4. Xiang, X.; Wang, Z.H.; Ye, L.L.; He, X.L.; Wei, X.S.; Ma, Y.L.; Li, H.; Chen, L.; Wang, X.R.; Zhou, Q. Co-infection of SARS-COV-2
and Influenza A Virus: A Case Series and Fast Review. Curr. Med. Sci. 2021, 41, 51–57. [CrossRef] [PubMed]
5. Konala, V.M.; Adapa, S.; Gayam, V.; Naramala, S.; Daggubati, S.R.; Kammari, C.B.; Chenna, A. Co-infection with Influenza A and
COVID-19. Eur. J. Case. Rep. Intern. Med. 2020, 7, 001656. [PubMed]
6. Buchy, P.; Badur, S. Who and when to vaccinate against influenza. Int. J. Infect. Dis. 2020, 93, 375–387. [CrossRef]
7. Liu, Y.; Morgenstern, C.; Kelly, J.; Lowe, R.; Jit, M. The impact of non-pharmaceutical interventions on SARS-CoV-2 transmission
across 130 countries and territories. BMC Med. 2021, 19, 40. [CrossRef]
8. Moore, J.P.; Klasse, P.J. COVID-19 Vaccines: “Warp Speed” Needs Mind Melds, Not Warped Minds. J. Virol. 2020, 94, e01083-20.
[CrossRef]
9. Wolff, G.G. Influenza vaccination and respiratory virus interference among Department of Defense personnel during the
2017–2018 influenza season. Vaccine 2020, 38, 350–354. [CrossRef] [PubMed]
10. Fink, G.; Orlova-Fink, N.; Schindler, T.; Grisi, S.; Ferrer, A.P.S.; Daubenberger, C.; Brentani, A. Inactivated trivalent influenza
vaccination is associated with lower mortality among patients with COVID-19 in Brazil. BMJ Evid. Based Med. 2020, in press.
[CrossRef]
11. Del Riccio, M.; Lorini, C.; Bonaccorsi, G.; Paget, J.; Caini, S. The Association between Influenza Vaccination and the Risk of
SARS-CoV-2 Infection, Severe Illness, and Death: A Systematic Review of the Literature. Int. J. Environ. Res. Public Health 2020,
17, 7870. [CrossRef]
12. Cocco, P.; Meloni, F.; Coratza, A.; Schirru, D.; Campagna, M.; De Matteis, S. Vaccination against seasonal influenza and socio-
economic and environmental factors as determinants of the geographic variation of COVID-19 incidence and mortality in the
Italian elderly. Prev. Med. 2021, 143, 106351. [CrossRef] [PubMed]
Vaccines 2021, 9, 529 16 of 17

13. Amato, M.; Werba, J.P.; Frigerio, B.; Coggi, D.; Sansaro, D.; Ravani, A.; Ferrante, P.; Veglia, F.; Tremoli, E.; Baldassarre, D.
Relationship between Influenza Vaccination Coverage Rate and COVID-19 Outbreak: An Italian Ecological Study. Vaccines 2020,
8, 535. [CrossRef] [PubMed]
14. Arokiaraj, M.C. Considering Interim Interventions to Control COVID-19 Associated Morbidity and Mortality-Perspectives. Front.
Public Health 2020, 8, 444. [CrossRef] [PubMed]
15. Marín-Hernández, D.; Schwartz, R.E.; Nixon, D.F. Epidemiological evidence for association between higher influenza vaccine
uptake in the elderly and lower COVID-19 deaths in Italy. J. Med. Virol. 2021, 93, 64–65. [CrossRef]
16. Martínez-Baz, I.; Trobajo-Sanmartín, C.; Arregui, I.; Navascués, A.; Adelantado, M.; Indurain, J.; Fresán, U.; Ezpeleta, C.; Castilla,
J. Influenza Vaccination and Risk of SARS-CoV-2 Infection in a Cohort of Health Workers. Vaccines 2020, 8, 611. [CrossRef]
17. De la Cruz Conty, M.L.; Encinas Pardilla, M.B.; Garcia Sanchez, M.; Gonzalez Rodriguez, L.; Muner-Hernando, M.L.; Royuela
Vicente, A.; Pintado Recarte, P.; Martinez Varea, A.; Martinez Diago, C.; Cruz Melguizo, S.; et al. Impact of Recommended
Maternal Vaccination Programs on the Clinical Presentation of SARS-CoV-2 Infection: A Prospective Observational Study. Vaccines
2021, 9, 31. [CrossRef]
18. Kissling, E.; Hooiveld, M.; Brytting, M.; Vilcu, A.M.; de Lange, M.; Martínez-Baz, I.; Sigerson, D.; Enkirch, T.; Belhillil, S.; Meijer, A.;
et al. Absence of association between 2019-20 influenza vaccination and COVID-19: Results of the European I-MOVE-COVID-19
primary care project, March-August 2020. Influenza Other Respir. Viruses in press.
19. Wells, G.A.; Shea, B.; O’Connell, D.a.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for
Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available online: http://www.ohri.ca/programs/clinical_
epidemiology/oxford.asp (accessed on 1 April 2021).
20. Rostom, A.; Dube, C.; Cranney, A. Rockville (MD): Agency for Healthcare Research and Quality (US). Available online: https:
//www.ncbi.nlm.nih.gov/books/NBK35156/ (accessed on 1 April 2021).
21. Massoudi, N.; Mohit, B. A Case–Control Study of the 2019 Influenza Vaccine and Incidence of COVID-19 among Healthcare
Workers. J. Clin. Immunol. 2021, 41, 324–334. [CrossRef]
22. Ragni, P.; Marino, M.; Formisano, D.; Bisaccia, E.; Scaltriti, S.; Bedeschi, E.; Grilli, R. Association between Exposure to Influenza
Vaccination and COVID-19 Diagnosis and Outcomes. Vaccines 2020, 8, 675. [CrossRef]
23. Belingheri, M.; Paladino, M.E.; Latocca, R.; De Vito, G.; Riva, M.A. Association between seasonal flu vaccination and COVID-19
among healthcare workers. Occup. Med. 2020, 70, 665–671. [CrossRef]
24. Vila-Córcoles, Á.; Ochoa-Gondar, O.; Torrente-Fraga, C.; Vila-Rovira, Á.; Satué-Gracia, E.; Hospital-Guardiola, I.; de Diego-
Cabanes, C.; Gómez-Bertomeu, F.; Basora-Gallisà, J. Evaluation of incidence and risk profile for suffering Covid-19 infection by
underlying conditions among middle-aged and older adults in Tarragona. Rev. Esp. Salud. Publica 2020, 94, e202006065.
25. Vila-Córcoles, A.; Ochoa-Gondar, O.; Satué-Gracia, E.M.; Torrente-Fraga, C.; Gomez-Bertomeu, F.; Vila-Rovira, A.; Hospital-
Guardiola, I.; de Diego-Cabanes, C.; Bejarano-Romero, F.; Basora-Gallisà, J. Influence of prior comorbidities and chronic
medications use on the risk of COVID-19 in adults: A population-based cohort study in Tarragona, Spain. BMJ Open 2020, 10,
e041577. [CrossRef]
26. Pawlowski, C.; Puranik, A.; Bandi, H.; Venkatakrishnan, A.J.; Agarwal, V.; Kennedy, R.; O’Horo, J.C.; Gores, G.J.; Williams, A.W.;
Halamka, J.; et al. Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with
recent non-COVID-19 vaccinations. Sci. Rep. 2021, 11, 4741. [CrossRef] [PubMed]
27. Jehi, L.; Ji, X.; Milinovich, A.; Erzurum, S.; Rubin, B.P.; Gordon, S.; Young, J.B.; Kattan, M.W. Individualizing Risk Prediction for
Positive Coronavirus Disease 2019 Testing: Results From 11,672 Patients. Chest 2020, 158, 1364–1375. [CrossRef] [PubMed]
28. Noale, M.; Trevisan, C.; Maggi, S.; Antonelli Incalzi, R.; Pedone, C.; Di Bari, M.; Adorni, F.; Jesuthasan, N.; Sojic, A.; Galli, M.;
et al. The Association between Influenza and Pneumococcal Vaccinations and SARS-Cov-2 Infection: Data from the EPICOVID19
Web-Based Survey. Vaccines 2020, 8, 471. [CrossRef] [PubMed]
29. Green, I.; Ashkenazi, S.; Merzon, E.; Vinker, S.; Golan-Cohen, A. The association of previous influenza vaccination and coronavirus
disease-2019. Hum. Vaccines Immunother. in press.
30. Conlon, A.; Ashur, C.; Washer, L.; Eagle, K.A.; Hofmann Bowman, M.A. Impact of the influenza vaccine on COVID-19 infection
rates and severity. Am. J. Infect. Control 2021, in press. [CrossRef] [PubMed]
31. Wilcox, C.R.; Islam, N.; Dambha-Miller, H. Association between influenza vaccination and hospitalisation or all-cause mortality
in people with COVID-19: A retrospective cohort study. BMJ Open. Respir. Res. 2021, 8, e000857. [CrossRef]
32. Yang, M.J.; Rooks, B.J.; Le, T.T.; Santiago, I.O., 3rd; Diamond, J.; Dorsey, N.L.; Mainous, A.G., 3rd. Influenza Vaccination and
Hospitalizations among COVID-19 Infected Adults. J. Am. Board Fam. Med. 2021, 34, S179–S182. [CrossRef]
33. Wouters, O.J.; Shadlen, K.C.; Salcher-Konrad, M.; Pollard, A.J.; Larson, H.J.; Teerawattananon, Y.; Jit, M. Challenges in ensuring
global access to COVID-19 vaccines: Production, affordability, allocation, and deployment. Lancet 2021, 397, 1023–1034. [CrossRef]
34. Deployment of COVID-19 Vaccines. Available online: https://en.wikipedia.org/wiki/Deployment_of_COVID-19_vaccines#
cite_note-world-total-18 (accessed on 10 April 2021).
35. Grubaugh, N.D.; Hanage, W.P.; Rasmussen, A.L. Making Sense of Mutation: What D614G Means for the COVID-19 Pandemic
Remains Unclear. Cell 2020, 182, 794–795. [CrossRef] [PubMed]
36. Wang, Q.; Yue, N.; Zheng, M.; Wang, D.; Duan, C.; Yu, X.; Zhang, X.; Bao, C.; Jin, H. Influenza vaccination coverage of population
and the factors influencing influenza vaccination in mainland China: A meta-analysis. Vaccine 2018, 36, 7262–7269. [CrossRef]
Vaccines 2021, 9, 529 17 of 17

37. Quach, T.H.T.; Mallis, N.A.; Cordero, J.F. Influenza Vaccine Efficacy and Effectiveness in Pregnant Women: Systematic Review
and Meta-analysis. Matern. Child Health J. 2020, 24, 229–240. [CrossRef] [PubMed]
38. Wilkinson, K.; Wei, Y.; Szwajcer, A.; Rabbani, R.; Zarychanski, R.; Abou-Setta, A.M.; Mahmud, S.M. Efficacy and safety of
high-dose influenza vaccine in elderly adults: A systematic review and meta-analysis. Vaccine 2017, 35, 2775–2780. [CrossRef]
39. Restivo, V.; Costantino, C.; Bono, S.; Maniglia, M.; Marchese, V.; Ventura, G.; Casuccio, A.; Tramuto, F.; Vitale, F. Influenza vaccine
effectiveness among high-risk groups: A systematic literature review and meta-analysis of case-control and cohort studies. Hum.
Vaccines Immunother. 2018, 14, 724–735. [CrossRef] [PubMed]
40. Cheng, Y.; Cao, X.; Cao, Z.; Xu, C.; Sun, L.; Gao, Y.; Wang, Y.; Li, S.; Wu, C.; Li, X.; et al. Effects of influenza vaccination on the risk
of cardiovascular and respiratory diseases and all-cause mortality. Ageing Res. Rev. 2020, 62, 101124. [CrossRef] [PubMed]
41. Martinez-Huedo, M.A.; Lopez-De-Andrés, A.; Mora-Zamorano, E.; Hernández-Barrera, V.; Jiménez-Trujillo, I.; Zamorano-Leon,
J.J.; Jiménez-García, R. Decreasing influenza vaccine coverage among adults with high-risk chronic diseases in Spain from 2014 to
2017. Hum. Vaccines Immunother. 2020, 16, 95–99. [CrossRef]
42. Tian, C.; Wang, H.; Wang, W.; Luo, X. Influenza vaccination coverage among US children from 2004/2005 to 2015/2016. J. Public
Health 2018, 41, e62–e69. [CrossRef]
43. Descamps, A.; Launay, O.; Bonnet, C.; Blondel, B. Seasonal influenza vaccine uptake and vaccine refusal among pregnant women
in France: Results from a national survey. Hum. Vaccines Immunother. 2020, 16, 1093–1100. [CrossRef]
44. Paget, J.; Caini, S.; Cowling, B.; Esposito, S.; Falsey, A.R.; Gentile, A.; Kyncl, J.; MacIntyre, C.; Pitman, R.; Lina, B. The impact of
influenza vaccination on the COVID-19 pandemic? Evidence and lessons for public health policies. Vaccine 2020, 38, 6485–6486.
[CrossRef]
45. Thindwa, D.; Garcia Quesada, M.; Liu, Y.; Bennett, J.; Cohen, C.; Knoll, M.D.; von Gottberg, A.; Hayford, K.; Flasche, S. Use of
seasonal influenza and pneumococcal polysaccharide vaccines in older adults to reduce COVID-19 mortality. Vaccine 2020, 38,
5398–5401. [CrossRef] [PubMed]
46. Netea, M.G.; Domínguez-Andrés, J.; Barreiro, L.B.; Chavakis, T.; Divangahi, M.; Fuchs, E.; Joosten, L.A.B.; van der Meer, J.W.M.;
Mhlanga, M.M.; Mulder, W.J.M.; et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 2020, 20,
375–388. [CrossRef]
47. Kleinnijenhuis, J.; Quintin, J.; Preijers, F.; Joosten, L.A.; Jacobs, C.; Xavier, R.J.; van der Meer, J.W.; van Crevel, R.; Netea, M.G.
BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clin. Immunol. 2014, 155, 213–219.
[CrossRef] [PubMed]
48. Walk, J.; de Bree, L.C.J.; Graumans, W.; Stoter, R.; van Gemert, G.J.; van de Vegte-Bolmer, M.; Teelen, K.; Hermsen, C.C.; Arts,
R.J.W.; Behet, M.C.; et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 2019, 10, 874.
[CrossRef] [PubMed]
49. Hui, K.P.Y.; Cheung, M.C.; Perera, R.; Ng, K.C.; Bui, C.H.T.; Ho, J.C.W.; Ng, M.M.T.; Kuok, D.I.T.; Shih, K.C.; Tsao, S.W.; et al.
Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and
conjunctiva: An analysis in ex-vivo and in-vitro cultures. Lancet Respir. Med. 2020, 8, 687–695. [CrossRef]
50. Stroup, D.F.; Berlin, J.A.; Morton, S.C.; Olkin, I.; Williamson, G.D.; Rennie, D.; Moher, D.; Becker, B.J.; Sipe, T.A.; Thacker, S.B.
Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) group. JAMA 2000, 283, 2008–2012. [CrossRef]