Influenza vaccination for healthcare workers who care for people aged 60 or older living in long‐term care institutions

Abstract

Rationale

People who work in long‐term care institutions (LTCIs), such as doctors, nurses, other health professionals, cleaners and porters (and also family visitors), may have substantial rates of influenza during influenza seasons. They often continue to work when infected with influenza, increasing the likelihood of transmitting influenza to those in their care. The immune systems of care home residents may be weaker than those of the general population; vaccinating care home workers could reduce transmission of influenza within LTCIs.

Objectives

To assess the effects of vaccinating healthcare workers in long‐term care institutions against influenza on influenza‐related outcomes in residents aged 60 years or older.

Search methods

We searched the Cochrane Central Register of Controlled Trials (via Cochrane Library), MEDLINE (via Ovid), Embase (via Elsevier), Web of Science (Science Citation Index‐Expanded and Conference Proceedings Citation Index ‐ Science), and two clinical trials registries up to 22 August 2024.

Eligibility criteria

In this version of the review we restricted eligibility to randomised controlled trials (RCTs) of influenza vaccination of healthcare workers (HCWs) caring for residents aged 60 years or older in LTCIs. Previously we included cohort or case‐control studies.

Outcomes

Outcomes of interest were: influenza (confirmed by laboratory tests) and its complications (lower respiratory tract infection; hospitalisation or death due to lower respiratory tract infection), all‐cause mortality, and adverse events.

Risk of bias

We used version one of the Cochrane risk of bias tool for RCTs.

Synthesis methods

Two review authors independently extracted data and assessed the risk of bias. We used risk ratios (RRs) with 95% confidence intervals (CIs) to summarise the effects of vaccination on our outcomes of interest. We accounted for clustering by dividing events and sample sizes for each study by an assumed design effect as part of a sensitivity analysis. We used GRADE to assess the certainty of evidence for our outcomes of interest.

Included studies

We did not identify any new trials for inclusion in this update. Four cluster‐RCTs from Europe (8468 residents) of interventions to offer influenza vaccination for HCWs caring for residents ≥ 60 years in LTCIs provided outcome data that addressed the objectives of our review. The average age of the residents was between 77 and 86 years, and most were female (70% to 77%). The studies were comparable in their intervention and outcome measures. The studies did not report adverse events. The principal sources of bias in the studies related to attrition, lack of blinding, contamination in the control groups, and low rates of vaccination coverage in the intervention arms, leading us to downgrade the certainty of evidence for all outcomes due to serious risk of bias.

Synthesis of results

Offering influenza vaccination to HCWs based in LTCIs may have little or no effect on the number of residents who develop influenza compared with those living in care homes where no vaccination is offered (from 5% to 4%) (RR 0.87, 95% CI 0.46 to 1.63; 2 studies, 752 participants; low‐certainty evidence).

We rated the evidence to be low from one study of 1059 residents showing a slight reduction in lower respiratory tract infection from HCW vaccination (6% versus 4%) (RR 0.70, 95% CI 0.41 to 1.2). The confidence interval is compatible with both a meaningful reduction and a slight increase in infections when illustrated as an absolute effect; 2% to 7%. Taking account of clustering for this outcome increased the confidence interval further, and we rated the evidence as very low‐certainty accordingly (RR 0.72, 95% CI 0.28 to 1.85). HCW vaccination programmes may have little or no effect on the number of residents admitted to hospital for respiratory illness (RR 1.02, 95% CI 0.82 to 1.27; 1 study, 3400 participants; low‐certainty evidence).

There is insufficient evidence to determine whether HCW vaccination impacts on death due to lower respiratory tract infections in residents: 2% of residents in both groups died from lower respiratory tract infections based on the RR of 0.82 (95% CI 0.45 to 1.49; 2 studies, 4459 participants; very low‐certainty evidence). HCW vaccination probably leads to a reduction in all‐cause deaths from 9% to 6% (RR 0.69, 95% CI 0.60 to 0.80; 4 studies, 8468 participants; moderate‐certainty evidence).

Authors' conclusions

The effects of HCW vaccination on influenza‐specific outcomes in older residents of LTCIs are uncertain. The reduction in all‐cause mortality in people observed could not be explained by changes in influenza‐specific outcomes. This review did not find information on co‐interventions with HCW vaccination: hand washing, face masks, early detection of laboratory‐proven influenza, quarantine, avoiding admissions, antivirals and asking HCWs with influenza or influenza‐like illness not to go to work. Better studies are needed to give greater certainty in the evidence for vaccinating HCWs to prevent influenza in residents aged 60 years or older in LTCIs. Additional studies are needed to further test these interventions in combination.

Funding

This review update received no dedicated funding. Previous versions of this review were supported by grants from the National Institute of Health Research (UK), and the National Health and Medical Research Council (Australia).

Registration

Protocol (2005): 10.1002/14651858.CD005187.pub

Original review (2006): 10.1002/14651858.CD005187.pub2

Update (2010): 10.1002/14651858.CD005187.pub3

Update (2013): 10.1002/14651858.CD005187.pub4

Update (2016): 10.1002/14651858.CD005187.pub5

Plain language summary

Flu vaccination for healthcare workers who care for people aged 60 or older living in long‐term care institutions

Key messages
Offering flu vaccination to people working in care institutions may make little or no difference to the number of residents who get flu or go to hospital with a chest infection, compared to those living in care institutions where no vaccination is offered.

Although we found that healthcare worker vaccination programmes led to fewer deaths due to any cause in residents of care institutions, we could not explain these results in terms of the reduction in flu or complications from chest infections.

What is flu?
Flu is a respiratory illness. It is spread by a family of viruses and can affect people of all ages. Residents in long‐term care institutions (LTCIs) are at a particularly high risk of being unwell with flu because their immune systems are weaker than people who live at home. People who work in LTCIs, such as doctors, nurses, other health professionals, cleaners and porters, may be exposed to flu during flu seasons. They often continue to work when they are infected with different respiratory viruses. This increases the likelihood of spreading them to those in their care. The signs and symptoms of flu are similar to those of many other respiratory illnesses. Therefore, it is important to test the effects of flu vaccination to prove by laboratory tests, which are highly accurate, whether residents in LTCIs actually have flu or another respiratory illness.

What did we want to find out?
We wanted to know if vaccinating healthcare workers against flu reduces the risk of flu and its complications in older residents in LTCIs.

What did we do?
We summarised existing research comparing different strategies to reduce flu in LTCIs. We looked for research studies which randomly assigned different care facilities to invite healthcare workers to receive flu vaccine at the start of the flu season or not.

What did we find?
We identified four studies which included data from 8468 residents. Healthcare workers from care homes in France and the UK were randomly assigned to be offered a flu vaccination. The studies provided information on flu, chest infections, hospital admission for a chest infection, and death. We were unable to identify information about unwanted effects in the studies. The average age of the care home residents was between 77 and 86 years, and the majority were female (between 70% and 77%).

Offering flu vaccination to healthcare workers who care for those aged 60 or over in LTCIs may have little or no effect on flu. We have little confidence in the effects of healthcare worker vaccination programmes on the number of residents with chest infections or the number of residents admitted to hospital due to chest infections. We have very little confidence in the evidence for the number of residents who died from chest infections. Although the number of residents who died from any cause was lower after healthcare worker vaccination, a reduction from 9% to 6%, we could not explain this effect in terms of changes to the number of people with flu or complications from chest infection.

What are the limitations of the evidence?
We were mainly concerned about how people were followed up, the impact of people in the studies being aware of whether they were vaccinated, the use of interventions in the control groups, and low rates of vaccination in the studies. In two studies, data could not be included from everyone who was recruited and this reduced our confidence in the results from those studies. This review did not find information on other interventions used in conjunction with vaccination of healthcare workers (for example, hand washing, face masks, early detection of laboratory‐proven flu, quarantine, avoiding new admissions, prompt antiviral use, asking healthcare workers with a flu‐like illness not to go to work).

How up to date is this evidence?
The evidence is current to 22 August 2024.

Summary of findings

Summary of findings 1. Summary of findings table.

Healthcare workers (HCWs) offered influenza vaccination compared with no vaccination: effects on influenza outcomes in people aged over 60 living in long‐term care institutions
Patient or population: people aged 60 or older living in long‐term care institutions Setting: Europe. Studies were conducted during influenza seasons (data from periods of high influenza activity) Intervention: HCWs offered vaccination Comparison: HCWs not offered vaccination
Outcomes	Anticipated absolute effects* (95% CI)		Risk Ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk in people living in care institutions where HCWs were not offered influenza vaccination	Risk in people living in care institutions where HCWs were offered influenza vaccination
Influenza Follow‐up to end of influenza season	Study population		RR 0.87 (95% CI 0.46 to 1.63)	752 (2 studies)	⊕⊕⊝⊝ Lowa,b
	5 per 100	4 per 100 (2 to 8)
Lower respiratory tract infection Follow‐up to end of influenza season	Study population		RR (0.7 (95% CI 0.41 to 1.2)	1059 (1 study)	⊕⊕⊝⊝ Lowa,b
	6 per 100	4 per 100 (2 to 7)
		4 per 100 (2 to 11)	RR 0.72 (95% CI 0.28 to 1.85)		⊕⊝⊝⊝ Very Lowa,c	Adjusted analysis included due to the difference in absolute effects shown when taking clustering into account.
Admission to hospital for respiratory illness Follow‐up to end of influenza season	Study population		RR 1.02 (95% CI 0.82 to 1.27)	3400 (1 study)	⊕⊕⊝⊝ Lowa,b
	9 per 100	9 per 100 (7 to 11)
Death from lower respiratory tract infection Follow‐up to end of influenza season	2 per 100	2 per 100 (1 to 3)	RR 0.82 (0.45 to 1.49)	4459 (2 studies)	⊕⊝⊝⊝ Very Lowa,b,d
Death from any cause	9 per 100	6 per 100 (5 to 7)	RR 0.69 (0.60 to 0.80)	8468 (4 studies)	⊕⊕⊕⊝ Moderatee
Adverse events	No studies reported on adverse events.
*The risk in the intervention group (and its 95% confidence interval (CI) is based on the assumed risk in the comparison group and the risk difference of the intervention (and its 95% CI) CI: confidence interval; HCW: healthcare worker; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded one level due to serious risk of bias: unclear risk of performance/detection bias and high rates of attrition.
^bDowngraded one level due to serious imprecision: confidence interval includes potentially important differences with either intervention. 
^cAdjusted analysis for the outcome of lower respiratory tract infection downgraded two levels due to very serious imprecision: confidence interval includes a very large increase in risk of infection with vaccination. 
^dDowngraded one level due to serious inconsistency. Some evidence of discordant direction of effects between the results of two studies in the analysis and I² indicating potentially moderate heterogeneity (56%). 
^eDowngraded one level due to serious risk of bias: high risk of attrition bias.

Background

Description of the condition

Residents in long‐term care institutions (LTCIs) may be cared for by a wide variety of physicians, nurses, care aides and nonmedical personnel, and have contact with many visitors and other residents in both their LTCI and when transferred to and from hospitals. Therefore, the key issues include the variability in influenza vaccination rates of LTCI residents, healthcare workers (HCWs) and visitors, and the effectiveness of vaccination. We wished to search for new randomised controlled trials (RCTs) to update the previous editions.

In this review, influenza means laboratory‐proven influenza because there is no 'non‐laboratory‐proven influenza'. A systematic review identified that less than 25% of cases assessed by family physicians as 'influenza‐like illness' (ILI) were later laboratory‐proven influenza; ILI is thus not a diagnostic term [1].

Vaccination rates of residents in LTCIs

A systematic review of studies mostly from North America and Europe found that for those aged 65 and older, rates of hospitalisation and mortality for influenza increased with age (and > 75 years compared to 65 to 74). Comorbidities were higher for residents of LTCIs than for community residents. Comorbidities were also higher by strain with A(H3N2), influenza B, and A(H1N1), in that order [2].

In the USA, vaccination rates in LTCIs vary between short‐stay and long‐stay residents, and by ethnicity. In a study of 630,373 short‐stay residents, the percentages who received an influenza vaccine were 67.2% of Caucasian residents, 55.1% of African‐American residents, and 54.5% of Hispanic residents. Of 1,029,593 long‐stay residents, 84.2%, 76.7%, and 80.8% of these resident groups, respectively, received an influenza vaccine [3].

A retrospective cross‐sectional study of residents assessed with the interRAI tool found variations in influenza vaccination rates for New Brunswick (Canada) (84% of 7006 residents in 64 homes), New Zealand (78.5% of 34,518 residents in 27 homes), the Netherlands (78.2% of 1508 residents in 30 homes) and Switzerland (65.4% of 2760 residents in 49 homes in 9 of 26 cantons) [4]. There were variations in vaccination rates within countries: New Zealand (standard deviation (SD) 3.7%), the Netherlands (SD 7.7%), New Brunswick (SD 8.3%) and Switzerland (SD 25.1%).

Older residents had severe cognitive impairment, health instability, and a greater number of medical comorbidities. Residents with a higher level of social engagement had higher vaccination rates. Residents who smoked tobacco or had aggressive behaviour were less likely to be vaccinated. These residents and those who decline vaccination are important targets for vaccination campaigns.

Even in these LTCIs, which are sufficiently equipped to use interRAI evaluation tools, 34.6% of Swiss residents (with wide variations between facilities), 21.5% of New Zealand residents, 21.8% of the Netherlands residents and 16% of New Brunswick residents were not vaccinated [4]. Strategies to increase rates in these unvaccinated residents need to be tested in randomised controlled trials (RCTs).

A systematic review of interventions to increase influenza vaccination rates of people aged 60 and older living in the community found significant positive effects of low‐intensity interventions (postcards), medium‐intensity interventions (personalised phone calls), and high‐intensity interventions (home visits, facilitators) that increased community demand for vaccination, enhanced access, and improved provider/system response. The overall GRADE assessment of the evidence was moderate quality. These interventions could be adapted for in‐person communication in LTCIs [5].

Vaccination efficacy can vary with vaccine dose, adjuvanted vaccines, ability to react to vaccination in people aged 65 years and over, and differences in vaccination rates between seniors living in the community and in institutions. Additional background on approaches to vaccinating LTCI residents and vaccination rates is included in Supplementary material 7.

HCWs LTCIs: RCTs for increasing influenza vaccination rates

Both mandatory and 'semi‐mandatory' approaches have been tried. A five‐year study of mandatory influenza vaccination of all HCWs at a large USA medical centre required all HCWs to either receive influenza vaccination or wear a mask at work during the influenza season if granted an exemption for religious or medical reasons. In the first year, out of 4703 HCWs, 4588 (97.6%) were vaccinated, and in years two to five, influenza vaccination rates were over 98%. Fewer than 0.7% of HCWs were granted exemptions and less than 0.2% refused vaccination and resigned from the medical centre [6].

In Finland, an Act in March 2017 stated that it is the employer’s responsibility to appoint only vaccinated HCWs to care for vulnerable patients, which is a semi‐mandatory statement. “An influenza vaccination shall also be administered to social welfare and health services staff and to medicinal care staff involved in the immediate treatment or care of patients or clients.” [7]. Based on a survey of 39 Finnish acute care hospitals, the mean influenza vaccination coverage in the 2017 to 2018 influenza season was 83.7% (SD 12.3); in the 2018 to 2019 season, vaccination coverage was 90.8% (SD 8.7) and in the 2019 to 2020 season, coverage was 87.6% (SD 10.9). Therefore, the semi‐mandatory policy did not provide complete coverage and there were wide variations between the hospitals [8].

In New South Wales, Australia, as of May 2024, all Category A workers and new recruits were required to receive one dose of the seasonal influenza vaccine annually [9]. There is as yet no follow‐up study.

A systematic review of interventions to increase vaccination rates of HCWs in LTCIs identified only two cluster‐RCTs which used interventions to improve all three main obstacles assessed by the authors as important (access, change opinions, and provide policy and leadership) and which the authors assessed as having strong quality on the Effective Public Health Practice Project’s (EPHPP) quality assessment tool for quantitative studies [10]. The first was a cluster‐RCT of free vaccinations on site, educational media, reminders for staff, and monitoring progress; this noted that HCP vaccination rates increased from 27.6% at baseline to 33.7% after the intervention, and in the control group, rates decreased from 24.2% to 22.9% [11]. The second was a cluster‐RCT of training nurses to promote vaccination and arrange vaccination sessions. This found that vaccination coverage for full‐time staff was 48.2% in intervention homes from 2003 to 2004, which declined to 43.2% from 2004 to 2005; in control homes, coverage declined from 5.9% to 3.5% [12].

A literature search identified one additional cluster‐RCT. The participants were nurses employed in 43 geriatric healthcare settings in France (n = 1335 intervention group; n = 1539 control group). The intervention was a slide show, posters, two booklets/leaflets, and rubber bracelets for staff. Random sequence allocation and allocation concealment were assessed to have an unclear risk of bias, incomplete outcome data and blinding of participants and personnel as a high risk of bias, and selective reporting of data as a low risk of bias. Only data for the nurses who participated were included. Assessed over one influenza season, nurses’ vaccination uptake increased from 33% to 49% in the intervention group and decreased from 36% to 27% in the control group [13].

Description of the intervention and how it might work

One way to prevent the spread of influenza to those residents aged 60 years or older in LTCIs is to fully vaccinate residents and HCWs.

The Centers for Disease Control (CDC) Advisory Committee on Immunisation Practices (ACIP) recommends that “adults aged ≥ 65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: high‐dose inactivated influenza vaccine (HD‐IIV3), recombinant influenza vaccine (RIV3), or adjuvanted inactivated influenza vaccine (aIIV3).” [14].

ACIP notes that “Older adults (aged ≥ 65 years) are at increased risk for severe influenza‐associated illness, hospitalization, and death compared with younger persons. Influenza vaccines are often less effective in this population. HD‐IIV, RIV, and aIIV have been evaluated in comparison with nonadjuvanted SD‐IIVs in this age group. Two of these vaccines, HD‐IIV and RIV, are higher dose vaccines, which contain an increased dose of HA antigen per vaccine virus compared with nonadjuvanted SD‐IIVs (60 μg for HD‐IIV3 and 45 μg for RIV3, compared with 15 μg for standard‐dose inactivated vaccines). The adjuvanted vaccine contains 15 μg of HA per virus, similarly to nonadjuvanted SD‐IIVs, but contains the adjuvant MF59.” [14].

ACIP then makes a carefully nuanced evaluation of the evidence: “HD‐IIV, RIV, and aIIV have shown relative benefit compared with SD‐IIVs in certain studies, with the most evidence available for HD‐IIV3. Randomized efficacy studies comparing these vaccines with nonadjuvanted SD‐IIVs against laboratory‐confirmed influenza outcomes are few in number and cover few influenza seasons.” [14].

ACIP also recommends:

“All persons aged ≥ 6 months without contraindications should be vaccinated annually. However, emphasis also should be placed on vaccination of persons who live with or care for those who are at increased risk for medical complications attributable to severe influenza… including … Health care personnel, including all paid and unpaid persons working in health care settings who have the potential for exposure to patients or to infectious materials. These personnel might include but are not limited to physicians, nurses, nursing assistants, nurse practitioners, physician assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff members, and others not directly involved in patient care but who might be exposed to infectious agents (e.g. clerical, dietary, housekeeping, laundry, security, maintenance, administrative, billing staff, and volunteers).” [14].

The immune systems of the elderly are less responsive to vaccination and vaccinating HCWs could reduce the exposure of those aged 60 years or older to influenza. HCWs are the key group who enter nursing homes and LTCIs on a daily basis.

Why it is important to do this review

This is an update of a Cochrane review first published in 2006 [15], and previously updated in 2010 [16], 2013 [17], and 2016 [18].

As individuals age, their resistance to and ability to cope with infections declines. They tend to acquire more multi‐morbidities and have more frequent admissions to hospitals. Transfers between LTCIs and hospitals expose them to new pathogens, patients, HCWs and visitors, all of whom need annual influenza vaccinations.

The exposure of elderly people to hospitals can be illustrated by a study of 129,443 first admissions of people aged 60 and older to the four acute‐care Calgary hospitals between 2013 and 2021. Of these, 12,144 died within six months, 64,441 had a second admission (9427 died), 35,206 a third admission (6500 died), 20,354 a fourth admission (4450 died) and 12,271 a fifth admission (2948 died), one had 38 admissions, and the oldest two patients were 108 [19].

The last edition of this review in 2016 concluded: “Our review findings have not identified conclusive evidence of benefit of HCW vaccination programmes on specific outcomes of laboratory‐proven influenza, its complications (lower respiratory tract infection, hospitalisation or death due to lower respiratory tract illness), or all‐cause mortality in people over the age of 60 who live in care institutions.” It is important that a comprehensive search of the literature be undertaken to identify any new evidence.

Objectives

To assess the effects of vaccinating healthcare workers in long‐term care institutions against influenza on influenza‐related outcomes in residents aged 60 years or older.

Methods

We conducted this review update in accordance with the Methodological Expectations of Cochrane Intervention Reviews (MECIR) Standards, and adhered to PRISMA 2020 for reporting [20].

We have made a number of changes to the scope of this review from the protocol. Our decision to no longer include non‐randomised studies reflects the high degree of bias associated with non‐randomised studies in this area: uptake of vaccination by healthcare workers (HCWs) varies considerably, and we believe that prospective studies with random assignment will emulate the policy decision around HCW vaccination more closely than other designs where the intervention group composition relies more heavily on vaccination uptake by HCWs.

Since the first version of this review we have restricted the types of outcome measures to reflect specific effects of the vaccine, which has led us to exclude measures of effect relating to influenza‐like illness (ILI). We have described the limitations of ILI‐outcomes in Supplementary material 6. As a response to the feedback submitted on our review in 2016, we reinstated the outcome of mortality due to any cause.

We decided to revert our analyses to relative effect measures (i.e. risk ratios) in preference to risk differences. Our intention had previously been to use measures of effect which conveyed effects in absolute terms. In response to peer‐reviewer feedback, we decided to base analyses on relative measures due to their property of stability in the presence of variable control group risk.

Criteria for considering studies for this review

Types of studies

Previous versions of this review included randomised controlled trials (RCTs). Non‐RCTs (cohort or case‐control studies) reporting exposure and outcomes by vaccine status were also eligible for inclusion. For the most recent version of this review, we have restricted inclusion to RCTs.

Types of participants

We included HCWs (nurses, doctors, nursing and medical students, other health professionals, cleaners, porters and volunteers who have regular contact with those aged 60 years or older), caring for those aged 60 years or older in institutions such as nursing homes, LTCIs or hospital wards.

Types of interventions

The intervention of interest was vaccination of HCWs with any influenza vaccine given alone or with other vaccines, in any dose, preparation or time schedule, compared with placebo or with no intervention. Studies on vaccinated elderly people are included in reviews looking at the effects of influenza vaccines in the elderly [21] and healthy adults [22].

Outcome measures

Critical outcomes

We used the following outcomes as the basis for our summary of findings table.

1. Cases of influenza in those aged 60 years or older, confirmed by viral isolation or serological supporting evidence (or both), plus a list of likely respiratory symptoms

2. Lower respiratory tract infection

3. Admission to hospital for respiratory illness

4. Deaths caused by lower respiratory tract infection

5. Deaths from any cause

6. Adverse events

The time points selected were taken at the last point of follow‐up reported by the trial authors. We excluded studies reporting only serological outcomes in the absence of symptoms. We did not consider outcomes for HCWs.

Important outcomes

Not applicable.

Search methods for identification of studies

This update includes searches up to 22 August 2024. All current search strategies are presented in Supplementary material 1. Details of previous search methods and strategies can be found in the 2016 update of our review [18].

Electronic searches

We searched the following databases on 22 August 2024.

1. The Cochrane Central Register of Controlled Trials (CENTRAL; 2024; Issue 8), via the Cochrane Library

2. MEDLINE via Ovid (1946 to 22 August 2024)

3. Embase via Elsevier (1947 to 22 August 2024)

4. Web of Science Core Collection Science Citation Index Expanded (SCI‐EXPANDED) and Conference Proceedings Citation Index ‐ Science (CPCI‐S) (1900 to 22 August 2024)

There were no language or publication status restrictions. We applied the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐maximising version (2023 revision); Ovid format, and in Embase (2023 revision); Embase.com format [23]. We adapted these search filters for the Web of Science search strategy.

Searching other resources

Searches of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov were updated (22 August 2024) to identify ongoing or recently completed trials (see Supplementary material 1). We searched bibliographies of retrieved articles and reviews and contacted trial authors for further details, if required. We further assessed the forward citations of previously included studies to identify records published since 2015 that may not have been found in the database searches.

Data collection and analysis

Selection of studies

Two review authors (TJL, RET) independently screened the titles and abstracts of retrieved records against the inclusion criteria. We resolved disagreements with a third review author (TOJ).

Data extraction and management

Two review authors (RET, TJL) applied the inclusion criteria to all identified and retrieved articles and extracted data from included studies into standard Cochrane Vaccines Field forms. We extracted the following data in duplicate.

1. Methods: purpose; design; period study conducted and statistics

2. Participants: country or countries of study; setting; eligible participants; age and gender

3. Interventions and exposure: in intervention group and control group

4. Outcomes of those aged 60 years or older residing in LTCFs

Two review authors (RET, TJL) independently checked data extraction. We resolved disagreements with a third review author (TOJ).

Risk of bias assessment in included studies

We carried out an assessment of methodological quality for RCTs using version one of the Cochrane risk of bias tool (RoB 1) [24]. We assessed selection bias (sequence generation and allocation concealment), performance and detection bias (blinding of key study personnel involved in the conduct and analysis of data for all outcomes), attrition bias (missing data for all outcomes), selective outcome reporting and other bias (both considered at the study level).

We looked for details of formal ethics approval and informed consent of participants.

Measures of treatment effect

We assessed the intervention effects using risk ratios (RR) with 95% confidence intervals (CI). The number‐needed‐to‐vaccinate was computed as 1/risk difference, where appropriate.

Unit of analysis issues

We intended to use adjusted data for all RCTs which had a cluster design. However, the availability of information on which to base adjustments for our critical outcomes was limited. We used data as reported (i.e. unadjusted) as the primary analysis, and used adjusted data as a sensitivity analysis. We adjusted data from cluster‐RCTs using standard methods as outlined in the Cochrane Handbook for Systematic Reviews of Interventions [25]. Briefly, we used a measure of the variation within and between clusters within each study (intracluster correlation coefficient (ICC)) to derive a study design effect for the results of each study. Adjusted estimates for cluster‐RCTs were derived by dividing the events and sample sizes in each treatment group with the study design effect to generate the 'effective sample size'. This was based on formulae described in full in the Cochrane Handbook for Systematic Reviews of Interventions [25]. We explored adjustment with imputed values in sensitivity analyses (see below).

Dealing with missing data

We did not use any strategies to impute missing outcome data and recorded missing data in the risk of bias table.

We contacted trial authors to ascertain the ICC and to confirm statistical analyses before proceeding to adjust events and totals to use in the analysis of data. In the absence of an ICC for two studies (Carman 2000 [26]; Potter 1997 [27]), we assumed an ICC of 0.023 based on a larger study (Hayward 2006 [12]).

Reporting bias assessment

We did not create a funnel plot to assess publication bias due to the small number of included studies.

Synthesis methods

Where we judged the studies to be comparable, we combined data in a statistical meta‐analysis. We meta‐analysed data with a Mantzel‐Haenschel random‐effects model because we expected some variation in the treatment effect due to the type of circulating virus, effectiveness of the vaccine administered to HCWs, and vaccine uptake.

Investigation of heterogeneity and subgroup analysis

We used the Chi² test and I² statistic to assess heterogeneity across the pooled studies. For outcomes where there was evidence of statistical variation (I² > 50% and a Chi² test with P ≤ 0.05), we proceeded with a meta‐analysis provided that the direction of the effects across the studies was consistent.

Whenever data presented in the study allowed it, we carried out subgroup analysis according to the vaccination status of residents aged 60 years or older. We assessed the following outcomes that arose during the influenza season.

1. Laboratory‐proven influenza infections (by paired serology, nasal swabs, reverse‐transcriptase polymerase chain reaction (RT‐PCR) or tissue culture)

2. Lower respiratory tract infection

3. Hospitalisation for respiratory illness

4. Death from respiratory tract illness

5. Death from any cause

6. Adverse events

Equity‐related assessment

We did not undertake an assessment of equity in this review.

Sensitivity analysis

We derived effective sample sizes and events for Carman 2000; Lemaitre 2009 [28]; and Potter 1997 using a correlation coefficient of 0.023 based on data reported by Hayward 2006. We report the results of adjusted analyses in the Synthesis of results.

Our original protocol outlined plans to consider the impact of risk of bias on the strength of findings through sensitivity analysis. Few of our analyses were able to combine data from two or more studies (see Supplementary material 4). This meant that sensitivity analysis was not a feasible way to explore the impact of removing studies at high risk of bias on our analyses. Our decisions relating to downgrading the certainty of evidence reflect the risk of bias judgements across the studies used in the analysis (see Risk of bias in included studies).

Certainty of the evidence assessment

One author (RET) assessed the certainty of evidence using GRADE methods. We created a summary of findings table using the following outcomes.

1. Cases of influenza

2. Lower respiratory tract infection

3. Admission to hospital for respiratory illness

4. Deaths caused by influenza or its complications

5. Deaths from any cause

6. Adverse events

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence as it related to the studies that contributed data to the meta‐analyses for the prespecified outcomes [29].

We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions [24], and used GRADEpro GDT software to rate the certainty of evidence [30]. Downgrading decisions for the randomised trial evidence resulted in one of four certainty ratings (high, moderate, low or very low) depending on the number of levels the evidence was downgraded. We justified all decisions to downgrade the certainty of evidence using footnotes in Table 1, and we made comments to aid the reader's understanding of the review where necessary.

Consumer involvement

There was no consumer involvement.

Results

Description of studies

Results of the search

The searches in this update covered publications up to 22 August 2024. We identified a total of 375 new records across the databases and trial registries, with an additional 328 identified through other sources (forward citations of previously included studies). Figure 1 shows the screening process for this update. We did not identify any new randomised controlled trials (RCTs) for inclusion from the 568 records screened (with duplicates removed).

1.

PRISMA flow diagram to illustrate the flow of studies through the different phases of the review

Previous searches in 2015, 2013, and 2009 identified (with duplicates removed) a total of 1841 papers (including 383 RCTs and 1443 observational studies). In the first publication of this review, we also examined 312 reports for detailed assessment from the review on the effects of influenza vaccines on the elderly [21].

Included studies

Four studies met the inclusion criteria. The studies were cluster‐RCTs from the UK and France and measured outcomes in a total of 8468 residents. The studies were conducted in care facilities where the residents were mainly female (70% to 77%) and whose average age was between 77 and 86 years. Three cluster‐RCTs contribute data to the influenza‐specific outcomes of interest to this review (Carman 2000; Lemaitre 2009; Potter 1997). The studies did not report on adverse events. Table 2 summarises the key characteristics of each study contributing to the synthesis of data in this review.

1. Overview of included studies and syntheses table.

Study type	Setting and year of study	Characteristics of care institution residents	Key features of intervention and control arms	Outcome measures used in the synthesis
Carman 2000 c‐RCT Some overlap of hospitals recruited in Potter 1997	20 long‐term care institutions in Scotland, UK Influenza season 1996/97	1437 residents; average age 82 years; 80% female	Intervention 620/1217 HCWs accepted vaccination in long‐term care hospitals. Day and night nurses, doctors, therapists, porters and ancillary staff (including domestic staff and ward cleaners) offered vaccination. Control 688 HCWs from control arm were not offered any vaccination.	Influenza Death from any cause
Hayward 2006 c‐RCT	44 care homes from northern, central & southern England, UK 2 periods of seasonal influenza (2003/4 & 2004/5)	2604 residents; average age 83 years; 71% female	Intervention 570/1610 HCWs accepted vaccination in care homes accepted in 2003/4 & 527/1726 HCWs accepted vaccination in 2004/5. Control 1674 HCWs & 1766 HCWs worked in care homes in control arm over the 2003/4 and 2004/5 periods, respectively.	Death from any cause
Lemaitre 2009 c‐RCT	40 nursing homes in Paris region, France Winter 2005/6	3483 residents; average age 86 years; 77% female	Intervention 678/989 HCWs accepted vaccination in care homes. Control 1015 HCWs worked in the care homes in the control arm.	Admission to hospital for respiratory infection Deaths from lower respiratory treact infection Death from any cause
Potter 1997 c‐RCT	12 long‐stay hospitals for older people in Scotland, UK in 1994	1059 residents; average age 77; 71% female	Intervention 654/1078 HCWs accepted vaccination. Day and night nurses and nursing auxiliaries, ward cleaners, doctors, therapists and porters. Control Information on number of HCWs at control sites not presented.	Influenza Lower respiratory tract infection Deaths from lower respiratory treact infection Death from any cause

HCWs: healthcare workers
c‐RCT: cluster‐randomised controlled trial

More detail for each of the included studies is presented in Supplementary material 2.

Effect estimates from Hayward 2006 were reported as rate differences per 100 residents, taking account of clustering. We decided not to use them in our analyses alongside data from the other studies for influenza‐specific outcomes because we cannot identify numerators reflecting individual residents. We were able to extract and use dichotomous data for death due to any cause.

Vaccination strategy and virological monitoring of patients

Carman 2000

Vaccination strategy: “Hospitals were randomly allocated to be offered routine vaccination of health‐care workers or not to be offered vaccination. Randomisation of clusters was balanced and stratified for policy for vaccination of patients and size of hospital. Hospitals were paired according to number of beds and policy for vaccination of patients, and one was chosen from each pair by random‐numbers table for health‐care workers to be vaccinated. Ten hospitals had a policy of vaccinating all consenting patients without contraindications, and in the other ten, the policy was to vaccinate primarily on request from patients or their relatives. Randomisation of sites was done by the study statistician…” (Carman 2000 p. 93).

Outcomes included virological monitoring of patients: “We selected a random sample of 50% of patients in each hospital for prospective virological monitoring. Randomisation was done centrally by computer‐generated random numbers… Detection of influenza A (H3 and H1) and B viruses by multiplex RT‐PCR was done with nested primer sets from the matrix gene regions.11 under optimum conditions.12 A nested PCR was done with TaqStart antibody.”

Lemaitre 2009

Vaccination strategy: “The campaign described the potential benefits of influenza vaccination for one’s own protection and that of the residents. Influenza vaccination was further recommended during face‐to‐face interviews with each member of staff present in the nursing homes between November 6 and December 15, 2006. The study team individually met all administrative staff, technicians, and caregivers to invite them to participate, and volunteers were vaccinated at the end of the interview.”

Outcomes included virological monitoring of patients: “Rapid diagnostic tests (Quick View Influenza Test; Quidel Corp., San Diego, CA) were distributed to each nursing home for use when clusters of ILI occurred in residents. When suspected clusters occurred, a team of monitors was sent to the nursing home to document signs and symptoms in all residents and staff and to record the results of the rapid diagnostic tests”

Potter 1997

Vaccination strategy: “Six hospitals had an "opt‐out" policy, in which patients were routinely given influenza vaccine unless they refused or had a major contraindication. Six hospitals had an "opt‐in" policy, in which patients were given vaccine only if they or their relatives requested it following ward advertisement of the availability of influenza vaccine. Hospital sites were stratified by unit policy for vaccination, then randomized for their HCWs to be routinely offered either influenza vaccination or no vaccination. This resulted in 4 hospital groups”

Outcomes included virological monitoring of patients: “A venous blood sample (10 mL) was taken from all consenting patients before vaccination and at the end of the study for assay of influenza A and B antibody by single radial hemolysis, using antigen from the 1993‐1994 season (on advice of the National Institute of Biological Standards and Control, Potters Bar, UK), which was closely related to the 1994‐1995 strain. Rising titers of antibodies to Mycoplasma pneumoniae were sought by complement fixation test. Blood samples have been analyzed only from unvaccinated patients in groups SVPO and SOPO. Vaccinated patients have not been included, as a rise in influenza antibody titer could be due to either vaccination or infection. Between the end of October 1994 and the end of March 1995 (5 months), patients were monitored for symptoms or signs of influenza‐like illness or lower respiratory tract infection. All deaths were recorded (including date and certified cause of death), as were all discharges from and admissions to the wards. The surveillance of patients was organized as follows: The ward nurses were asked to notify 1 of 2 research nurses (by radiopage or answering machine) if any patients under their care developed clinical symptoms suggestive of upper respiratory tract viral illness, influenza, or lower respiratory tract infection. The research nurse then visited the patient (within 24 h of referral) to record symptoms, clinical signs, and results of available relevant investigations using standardized forms. Chest radiographs were not included as part of the routine assessment of suspected lower respiratory tract infection, as for many of the peripheral hospitals, it would have required an ambulance journey for the patient. Patients with suspected viral illness who gave verbal consent had a nasopharyngeal aspirate (NPA) sample obtained within 48 h of notification of symptoms. IFA for influenza A and B, respiratory syncytial virus (RSV), Chlamydia psittaci, and adenovirus antigens in epithelial cells was done using kits (Dako, High Wycombe, UK). Patients were revisited by the research nurses 2‐3 days later to assess, by standard means, possible development of lower respiratory tract infection.”

Hayward 2006

Vaccination strategy: “We carried out a pair matched cluster randomised controlled trial of promotion and delivery of influenza vaccine to care home staff over the winters of 2003‐4 and 2004‐5, with collection of aggregate data on outcomes among residents. The study was carried out in a large private chain of UK care homes.”

“For the purposes of the study the company agreed to adopt a policy for influenza vaccination of staff in randomly selected intervention homes while maintaining their usual policy of not actively promoting staff vaccination in control homes”

Outcomes did not include virological monitoring of patients: “Outcomes were measured in residents and collected as aggregate data within each home. The primary outcome was all‐cause mortality of residents. Secondary outcomes were influenza‐like illness, mortality with influenza‐like illness, admissions to hospital from any cause, admissions to hospital with influenza‐like illness, and consultations with a general practitioner for influenza‐like illness.”

Ethics approval

Carman 2000, Hayward 2006, Lemaitre 2009 and Potter 1997 received formal ethics approval. Hayward 2006 obtained ethics approval from a local multicentre research ethics committee. Carman 2000 and Potter 1997 obtained written informed consent from healthcare workers (HCWs) and witnessed verbal consent from participants for nose swabs to be taken, and Potter 1997 also did this for blood samples. The LTCIs already had policies for opting in or out of influenza vaccination. Lemaitre 2009 obtained face‐to‐face informed consent from HCWs.

Excluded studies

We excluded all 747 new citations identified in the 2013 review update, the 379 from the 2015 searches, and the 568 from the 2024 searches as they either did not have influenza vaccination outcome data for those aged 60 years or older or for HCWs (or both), did not report the outcome data we specified, or reported only influenza antibody levels (Supplementary material 3).

We excluded one previously included non‐randomised study, due to the change in eligibility criteria for this update (Oshitani 2000 [31]).

Risk of bias in included studies

See the risk of bias tables (Figure 2). We downgraded the certainty of evidence for each of the outcomes of interest due to risk of bias arising from lack of blinding or attrition bias.

2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study

There was adequate sequence generation in three studies. One used a random numbers table (Carman 2000), one used a centralised random numbers generator (Lemaitre 2009), and for the third study we considered that the process was likely to have been carried out reliably (Hayward 2006). However, there was uncertainty in one study: "Hospital sites were stratified by unit policy for vaccination, then randomised for their healthcare workers to be routinely offered either influenza vaccination and patients unvaccinated..." (Potter 1997).

No study explicitly stated that they had appropriate means of blinding participants or study personnel to vaccination. In Carman 2000 and Potter 1997 there is no statement that any researcher, assessor, data analyst, HCW or participant was blinded. In Carman 2000 the study nurses "took additional opportunistic nose and throat swabs from non‐randomised patients who the ward nurses thought had an influenza‐like illness". In Potter 1997 ward nurses paged the research nurses "if any patients under their care developed clinical symptoms suggestive of upper respiratory tract viral illness, influenza, or lower respiratory tract infection," and in Lemaitre 2009 "Influenza vaccination was further recommended during face‐to‐face interviews with each member of staff ... The study team individually met all administrative staff, technicians and caregivers to invite them to participate and volunteers were vaccinated at the end of the interview." One of the four cluster RCTs had a low risk of bias arising from missing data (Lemaitre 2009). For the remaining three studies, we judged the risk of attrition bias to be high. No study appeared to report results selectively.

Other possible sources of bias identified which could not be assigned to the bias domains of selection, performance, attrition or reporting of outcomes were as follows for Potter 1997.

• There were inconsistencies in outcome gradients (Table 3). In the population under observation, Potter 1997 reported 216 cases of suspected viral illness, 64 cases of influenza‐like illness, 55 cases of pneumonia, 72 deaths from pneumonia and 148 deaths from all causes. In the subpopulation of both vaccinated staff and patients, Potter 1997 reported 24 cases of suspected viral illness, two cases of influenza‐like illness, seven cases of pneumonia, 10 deaths from pneumonia and 25 deaths from all causes. As these gradients are not plausible (one would expect a greater proportion of cases of influenza‐like illness to be caused by influenza during a period of high viral activity), the effect on all‐cause mortality is likely to reflect bias rather than a real effect of vaccination.

• 67% of staff in active arm one and 43% in active arm two were vaccinated.

• There is no description of the vaccines administered, vaccine matching or background influenza epidemiology.

2. Outcome gradients from Potter 1997.

	SVPV	SVP0	S0PV	S0P0
Suspected viral illness	24	58	75	59
Influenza‐like illness	2	20	19	23
Pneumonia	7	14	16	18
Deaths from pneumonia	10	15	24	23
All deaths	25	25	56	42

S0P0: staff and patients not vaccinated
S0PV: staff not vaccinated, patients vaccinated
SVPV: staff and patients vaccinated
SVP0: staff vaccinated and patients not vaccinated

For Carman 2000 potential sources of bias were as follows.

• The total number of long‐term care hospitals in West and Central Scotland is not stated. In the long‐term care hospitals in which HCWs were offered vaccinations, residents had higher Barthel scores.

• 51% of healthcare workers in the Lemaitre 2009 arm received vaccine in the long‐term care hospitals where vaccine was offered and 4.8% where it was not; 48% of patients received vaccine in the arm where HCWs were offered vaccinations and 33% in the arm where HCWs were not.

• The analysis was not corrected for clustering, unlike the Potter 1997 pilot; in the long‐term care hospitals where HCWs were offered vaccination, the patients had significantly higher Barthel scores and were more likely to receive influenza vaccine (no significance level stated). Due to missing data, these differences could not be accounted for other than by estimation. Statistical power may also have been a problem as the detection rate of 6.7% was lower than the estimated rate of 25% used in the power calculation.

The Potter 1997 and Carman 2000 studies took place in the same geographical area with a modest possible but unknown overlap of staff and residents. Only three of the long‐term care hospitals in the Potter 1997 study were included in the Carman 2000 cluster‐RCT because some of the homes were closed down (e‐mail communication from Dr. Stott) but the continuity of staff between the institutions is unknown.

Synthesis of results

The main findings of the review are presented in Table 1. Supplementary material 4 lists all the analyses we undertook. The download of data is available from Supplementary material 5.

1. Cases of influenza in those aged 60 years or older confirmed by viral isolation or serological supporting evidence (or both), plus a list of likely respiratory symptoms

Potter 1997 reported outcomes only for unvaccinated patients. Carman 2000 reported data on influenza cases amongst vaccinated and unvaccinated patients combined. We were able to pool the results for Carman 2000 and Potter 1997, and we computed an overall risk ratio (RR) of 0.87, 95% CI 0.46 to 1.63; 2 studies, 752 participants; low‐certainty evidence (Figure 3). The pooled RR based on adjusted study effect estimates was 0.93, 95% CI 0.42 to 2.08.

3.

Forest plot (1.1 Influenza)

2. Lower respiratory tract infection

Only Potter 1997 reported data for lower respiratory tract infection and reported results separately for vaccinated and unvaccinated patients. For the vaccinated and unvaccinated patients combined, we computed an RR of 0.70, 95% CI 0.41 to 1.2; 1 study, 1059 participants; low‐certainty evidence (Figure 4). The pooled RR taking account of clustering was 0.72, 95% CI 0.28 to 1.85. We rated the certainty of evidence for the adjusted estimate as very low due to the impact of the wider CI on the absolute effects (see Table 1).

4.

Forest plot (1.2 Lower respiratory tract infection)

3. Admission to hospital for respiratory illness

Only Lemaitre 2009 provided data for admission to hospital for respiratory illness and reported similar rates of admission in both arms (RR 1.02, 95% CI 0.82 to 1.27; 1 study, 3400 participants; low‐certainty evidence; Figure 5). The pooled RR based on adjusted study effect estimates was RR 1.03, 95% CI 0.76 to 1.39).

5.

Forest plot (1.3 Admission to hospital for respiratory illness)

4. Deaths caused by lower respiratory tract infection

Potter 1997 reported data for deaths from pneumonia separately for vaccinated patients and unvaccinated patients. Lemaitre 2009 reported results for "deaths from respiratory illness" (not further defined) for vaccinated and unvaccinated patients combined. The RR was 0.82, 95% CI 0.45 to 1.49; 2 studies, 4459 participants; very low‐certainty evidence (Figure 6). Adjustment for the effect of clustering gave an RR of 0.86, 95% CI 0.42 to 1.76.

6.

Forest plot (1.4 Deaths from lower respiratory tract infection )

5. Deaths from any cause

Potter 1997 reported outcomes separately for vaccinated patients and unvaccinated patients. Carman 2000, Hayward 2006 and Lemaitre 2009 reported data for vaccinated and unvaccinated patients combined. There was a reduction in all‐cause mortality in residents in intervention arms where influenza vaccination was offered to HCWs (RR 0.69, 95% CI 0.60 to 0.80; 4 studies, 8468 participants; moderate‐certainty evidence; Figure 7). Taking account of clustering gave an RR of 0.7, 95% CI 0.59 to 0.84.

7.

Forest plot (1.5 Death from any cause)

6. Adverse events

No studies reported this outcome.

Equity assessment

We did not perform an equity assessment.

Reporting biases

There were insufficient studies identified to enable us to determine small study effects reliably by a funnel plot.

Discussion

Summary of main results

Four cluster‐randomised controlled trials (RCTs) conducted in the UK and France met our criteria. Our review did not find evidence that vaccination led to reductions in laboratory‐proven influenza, admissions to hospital for lower respiratory tract illness, and deaths from lower respiratory tract illness (Potter 1997), with the 95% confidence interval (CI) in each case including unity. There is moderate‐certainty evidence of a reduction in all‐cause mortality from 9% to 6%, although this was not explained by reductions in influenza, respiratory‐related mortality or hospitalisations.

Limitations of the evidence included in the review

We downgraded the certainty of evidence for each outcome due to serious risk of bias (Table 1). There were low rates of vaccination of HCWs and some vaccination of HCWs in control groups (notably Potter 1997). A key uncertainty for all outcomes other than death from any cause is imprecision arising from wide confidence intervals around the estimated effects. We downgraded the evidence for the effect of HCW vaccination on death due to respiratory infections for inconsistency, as there was some evidence of discordant direction of effects between the results of two studies in the analysis and I² potentiallyindicates moderate heterogeneity (56%). The analysis of both adjusted and unadjusted study results for the five outcomes of interest were consistent with each other. We discuss the consequences of our choice of effect measure below.

Four cluster‐RCTs focused directly on the question of the effect of HCW vaccination on the mortality and morbidity of long‐term care institution (LTCI) residents aged 60 years or older. The cluster‐RCTs have certain common features: they are all underpowered to detect any difference in influenza mortality, which is a rare event. All participants, were they residents or carers, were unblinded to their intervention status. All trials showed little effect on influenza or its complications (the registered indication for the vaccines). Our review has yielded no clear indication of benefit on specific outcome measures of influenza. The reduction in mortality from any cause was downgraded due to bias, and we could not identify a mechanism for this effect from the other outcomes showing a reduction in influenza morbidity. It is noteworthy that the studies did report significant results for a syndrome (influenza‐like illness (ILI)), which is caused only in part by influenza viruses. The absence of usable outcome data for the specific effects of HCW vaccination programmes from Hayward 2006 restricts the applicability of our findings further.

Limitations of the review processes

We are aware that our reliance on unadjusted data for our primary analysis may underestimate the error for the confidence intervals across the individual studies, and therefore underestimate the amount of statistical variation across our summary estimates. Furthermore, in adjusting for this unit of analysis error in our sensitivity analyses, our choice of intracluster correlation coefficients for two of the studies were based on the estimate provided by Hayward 2006. Although the recalculation of the effective sample size was done in accordance with recommended procedures [25], we have assumed that the adjustment required is the same across the outcomes extracted for each study: this assumption may not hold.

Our decision to combine data for the outcome of death from lower respiratory tract infection could be questioned. There is some evidence of qualitative heterogeneity (discordant direction of effects across the studies) and statistical heterogeneity as estimated by I² (Analysis 1.4). The P value of the Chi² test indicates that there is insufficient evidence to determine statistical heterogeneity, but it does not rule this out. With only two studies contributing data to this analysis, the test has low power to detect important levels of heterogeneity, and gives us no grounds to explain it reliably.

Agreements and disagreements with other studies or reviews

Ahmed and colleagues identified the same cluster‐RCTs that we did and rated the certainty of evidence for many influenza‐specific outcomes as 'low' and 'very low', which is compatible with our assessments, although we have downgraded for different reasons [32]. The evidence for non‐specific outcomes was graded as moderate certainty.

Ahmed included three observational studies that we excluded: Bénet 2012 [33] (cannot separate outcomes for those aged ≥ 60 years), Enserink 2011 [34] (outcome measure is ILI) and Wendelboe 2011 [35] (problems in design and execution such that the results cannot be relied on). Both our review and Ahmed's used laboratory‐confirmed influenza as an outcome. However, the other outcomes we assessed were specific to influenza (hospitalisation for influenza and deaths from influenza) whereas Ahmed used non‐specific outcomes (all‐cause hospitalisation and all‐cause deaths). We also assessed lower respiratory tract infection.

An important question is the contribution that influenza vaccination of people aged 60 years or older makes in reducing total annual mortality, and several studies have assessed this issue. A population study used data from the US national multiple‐cause‐of‐death databases from 1968 to 2001 and found that for those aged 65 years or older, mortality attributable to pneumonia or influenza never exceeded 10% of all deaths during those winters [36]. A study of 11,240 Spanish community‐dwelling elderly people, conducted between January 2002 and April 2005, found the attributable mortality risk in individuals not vaccinated against influenza was 24 deaths/100,000 person‐weeks within influenza periods [37]. Vaccination prevented 14% of these deaths for the population and one death was prevented for every 239 annual vaccinations (ranging from 144 in winter 2005 to 1748 in winter 2002). It should be noted that these data are not for residents of LTCIs. A mathematical model predicted that for a 30‐bed unit, an increase in HCW vaccination rates from 0% to 100% would decrease resident influenza infections by 60% [38].

Authors' conclusions

Implications for practice

The effects of healthcare worker (HCW) vaccination on influenza‐specific outcomes in older residents of long‐term care institutions are uncertain. The four cluster‐randomised controlled trials included in our review are at high risk of bias and are underpowered for influenza (low‐certainty evidence), lower respiratory tract infections (low‐certainty evidence), admissions to hospital (low‐certainty evidence), and deaths from lower respiratory tract illness (very low‐certainty evidence).

We judged the certainty of evidence for the reduction in all‐cause mortality observed with HCW vaccination to be moderate due to risk of bias. We are unable to reconcile the lower rate of all‐cause mortality following HCW vaccination with the lack of a clear effect on influenza morbidity. Influenza deaths are a small part of overall mortality in age groups over 60 and, therefore, all‐cause death rates should be interpreted with caution when considering the impact of influenza vaccination in this group.

Equity‐related implications for practice

We did not perform an equity assessment.

Implications for research

The randomised controlled trials (RCTs) of healthcare worker (HCW) vaccination in long‐term care institutions (LTCIs) have yet to provide a robust evidence base to guide decision‐making. Future RCTs need to take into account the following challenges in the design and implementation of interventions studied, and the conduct of studies in LTCIs.

The clinical and research communities have been waiting a long time for a definitive cluster‐RCT of HCW influenza vaccination in LTCIs. It is important that it is comprehensive and controls for all possible alternative explanations other than HCW vaccination rates for LTCI residents’ influenza illnesses.

1. Low HCWs rates of influenza vaccination. Apply existing research on reducing barriers to develop comprehensive evidence‐based interventions involving all hospital staff in both the development and presentation of the interventions. Some LTCIs have higher vaccination rates of > 80%. LTCIs with the lowest rates may need initial individual and group incentives.

2. Low rates of influenza vaccination of LCTI residents. Apply existing research on reducing barriers to develop comprehensive evidence‐based interventions involving all hospital staff in both the development and presentation of the interventions. Involve family members and carers. Identify and solve policy, leadership and administrative reasons for LTCIs with low rates. Identify non‐vaccinated residents in the literature and in individual LTCIs, and develop interventions to increase their rates, including vaccine refusers.

3. Health systems experience multiple transfers between the community, LTCIs and hospitals and the vaccination status of patients and HCWs in each is important to prevent transfers of infected persons to LTCIs. Home HCWs care for multimorbid elderly patients who may be admitted to an LTCI directly or via a hospital and thus influence influenza rates. The vaccination status of these workers is thus relevant to the overall influenza transmission rate in hospitals. An analysis of a random sample of US national Home Health Care surveys between 2018 and 2019 found that 26% of agencies required staff influenza vaccination and 71% reported staff influenza vaccination rates of ≥ 75%. Half of the agencies provided free vaccinations on site [39].

4. Inadequate influenza vaccination rates of elderly people in the community. There is considerable scope for increasing influenza vaccination rates in community‐dwelling older people and the next major study could contemplate a community intervention arm as part of the LTCI cluster‐RCT to increase rates in community‐dwelling older people, so when they are admitted to an LTCI they are vaccinated.

5. Quarantine of patients before admittance to LTCIs. The next RCT could consider an intervention arm of quarantining people before admittance to LTCIs.

Implications for research: suggestions for future research designs

Future cluster‐RCTs of influenza vaccination of HCWs should control for known reasons for as many changes as possible in LTCI residents’ influenza rates from environmental and organisational influences, then provide evidence at low risk of bias for each of these PICO criteria.

• Population: all patients, HCWs and visitors to the institutions in the intervention and control groups.

• Interventions in intervention group LTCIs: influenza vaccination of all HCWs (including all staff who share space and air circulation with residents). Frequent monitoring of hand washing and face mask use. Laboratory tests for all HCWs during influenza season and require HCWs with influenza to stop work. Proof of influenza vaccination of all visitors. An experiment in a small simulated ward without patients or staff found that a combination of a positive and negative oxygen ion purifier (PNOI) and a HEPA filter achieved 100% purification rates after 30 minutes against H1N1‐pr8 influenza. Before the major cluster‐RCT is conducted, real‐world experiments in fully staffed wards should be conducted to test filter combinations [40]. Another intervention arm could use a rapid quarantine unit for rapid pathogen testing for new residents and residents transferred from hospital.

• Comparison: LTCIs usual care and influenza vaccination protocol.

• Outcomes: influenza vaccination rates of HCWs and patients. Laboratory testing for pathogens (influenza, respiratory syncytial virus, pneumococcus, SARS, other respiratory pathogens – rhinovirus is a major co‐infection); detailed independent assessment of pre‐hospital and hospital clinical records; comorbidities, laboratory tests (blood cultures, white blood cell counts, other laboratory results) cause of hospitalisation; lower respiratory tract infection (imaging), and cause of death. The cluster‐RCTs included in the current review provided incomplete evidence because they did not provide comprehensive assessments of cause of death (ideally this would be independently conducted by two physicians).

Equity‐related implications for research

The included RCTs were only conducted in France and the UK and not in other countries at different World Health Organization stages of development. No patient characteristics were measured, such as ethnicity or socio‐economic status, and the studies did not include institutions.

Supporting Information

Supplementary materials are available with the online version of this article: 10.1002/14651858.CD005187.pub5.

Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

Supplementary material 1 Search strategies

Supplementary material 2 Characteristics of included studies

Supplementary material 3 Characteristics of excluded studies

Supplementary material 4 Analyses

Supplementary material 5 Data package

Supplementary material 6 Reasons not to use influenza‐like illness in assessing the effectiveness of influenza vaccines

Supplementary material 7 Approaches to vaccinating residents of long‐term care institutions and vaccination rates of healthcare workers

New search for studies and content updated (no change to conclusions)

Additional information

Contributions of authors

Responsible for the design of the review: Roger Thomas (RET), Tom Jefferson (TOJ).
Responsible for search methods and conduct: Stan Earnshaw (SE).
Responsible for data extraction: RET, TOJ, Toby Lasserson (TJL).
Responsible for the assessment of study quality and outcomes: RET and TJL.
Responsible for the first draft: RET.
Responsible for the final draft: RET, TOJ, TJL, SE.

The following authors were involved in previous published versions of this review in 2005 and 2006, and are no longer included in the author byline: Vittorio Demicheli and Daniela Rivetti. Some of the content retained in this review reflects their contributions.

Declarations of interest

Dr Roger Thomas: no declarations of interest.
Toby Lasserson is an employee of Cochrane and is an associate editor of the journal 'Research Integrity and Peer Review'. TJL was not involved in the editorial process of the article.
Dr Tom Jefferson's disclosure is here.
Stan Earnshaw: no declarations of interest.

Sources of support

Internal sources

• None, Other

  No support

External sources

• No sources of support provided

Registration and protocol

Protocol (2005): 10.1002/14651858.CD005187.pub

Original review (2006): 10.1002/14651858.CD005187.pub2

Update (2010): 10.1002/14651858.CD005187.pub3

Update (2013): 10.1002/14651858.CD005187.pub4

Update (2016): 10.1002/14651858.CD005187.pub5

Data, code and other materials

The following are available to download by Cochrane Library users.

• Full search strategies for each database; full citations of each unique report for all studies included, ongoing or awaiting classification, or excluded at the full‐text screen, in the final review

• Study data, including study information, study arms, and study results

• Consensus risk of bias assessments; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows

Appropriate permissions have been obtained for such use where needed. Analyses were conducted with Cochrane’s authoring tool, Review Manager, using inbuilt computation methods [41].

What's new

Date	Event	Description
27 February 2025	New search has been performed	No new trials were identified for inclusion or exclusion in this 2024 update.
27 February 2025	New citation required but conclusions have not changed	Searches updated 22 August 2024. Eligibility criteria changed to include only RCTs.

History

Protocol first published: Issue 2, 2005
Review first published: Issue 3, 2006

Date	Event	Description
11 March 2016	Feedback has been incorporated	Feedback comment added to the review
27 October 2015	New search has been performed	Searches conducted on 27 October 2015 identified 153 RCTs and 236 observational studies but no new studies were identified for inclusion in this update. We excluded five new trials (Amodio 2014 [42]; Bénet 2012; Enserink 2011; Riphagen‐Dalhuisen 2013 [43]; Wendelboe 2011). We searched clinical trials registries on 27 January 2016 and identified 11 citations, but no new studies were identified for inclusion.
27 October 2015	New citation required but conclusions have not changed	Our conclusions remain unchanged.
31 March 2013	New search has been performed	Searches conducted. We identified 268 RCTs and 479 observational studies and no new studies were included in this 2013 review update.
31 March 2013	New citation required but conclusions have not changed	Based on our literature review, we now determine that two outcome measures, influenza‐like illness (ILI) (Supplementary material 6) and all‐cause mortality, reported in the first and second publications of this review, are inappropriate measures of influenza vaccine effectiveness. They are not registered indications for the vaccine. Therefore, the outcome data from Hayward 2006 (main outcome measure all‐cause mortality and secondary outcome measure ILI) and Oshitani 2000 (outcome measure ILI) are no longer presented.
10 December 2009	Feedback has been incorporated	Feedback comment and reply added.
21 June 2008	Feedback has been incorporated	Feedback comment added.
13 May 2008	Amended	Converted to new review format.
23 May 2006	New search has been performed	Review first published, Issue 3, 2006.