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Abstract

Vaccination is the most practical means available for preventing influenza. Influenza vaccines require frequent updates to keep pace with antigenic drift of the virus, and the effectiveness, and sometimes the safety, of the vaccine can therefore vary from season to season. Three key populations that the World Health Organization recommends should be prioritized for influenza vaccination are pregnant women, children younger than 5 years of age and the elderly. This review discusses the burden of influenza and the safety and effectiveness profile of influenza vaccines recommended for these groups.

Keywords

influenza vaccination child pregnancy aged safety efficacy effectiveness immunogenicity reactogenicity

Introduction

Each year, influenza is a significant cause of morbidity and mortality in the community. Prevention by vaccination is a cost-effective and minimally disruptive method of preventing influenza.^1,2 The influenza vaccine is unique among vaccines in requiring annual readministration and providing brief immunity. Moreover, the composition of the vaccine needs to be frequently updated owing to the continuously changing antigenic structure of the virus. The choice of influenza strains to include in the vaccine is decided once per year for each hemisphere, allowing manufacturers about 6 months to develop, test, license and sell the new vaccine, leaving no time for large randomized controlled trials (RCTs) to test efficacy. Thus, immunogenicity studies are widely accepted as a proxy for efficacy.³ A major limitation of these studies is that they are unable to provide estimates for the number of influenza cases prevented by vaccination and neither immunogenicity studies nor RCTs can estimate vaccine effectiveness (VE) in the community.⁴ Observational studies can provide VE estimates,⁵ and in recent years a number of investigators from Europe,⁶ Spain,⁷ the UK,⁸ the USA,⁹ Canada¹⁰ and Australia,¹¹ have conducted ongoing observational studies to monitor influenza VE.

The World Health Organization (WHO) lists several key populations as target groups for influenza vaccination: pregnant women, children younger than 5 years, the elderly and individuals with underlying health conditions such as HIV/AIDS, asthma or chronic heart or lung diseases that place them at increased risk of a severe outcome. In countries such as Australia, Canada and the UK, influenza vaccine is provided free through government programmes for some or all of those in these target groups. The rationale for vaccination recommendations typically follows one of two approaches: (a) a risk-based approach whereby those most likely to suffer a severe outcome of influenza infection are targeted to reduce the impact of influenza; (b) a transmission-based approach that aims to reduce the spread of the virus by targeting key groups implicated in transmission (e.g. children) to limit spread for other vulnerable groups (e.g. the elderly).¹²

The choice of vaccines to use in these programmes results from a process that balances immunogenicity, efficacy or effectiveness data and safety. For example, while some enhanced vaccines may elicit higher rates of protection, they may also result in higher levels of adverse events following immunization (AEFI). Therefore, vaccine licensing and recommended use may vary among age groups and for specific risk groups. In this review, we discuss the burden, safety and effectiveness of influenza vaccines for three key target groups, that is, the elderly, children, and pregnant women. Table 1 summarizes our key points.

Table 1.

A summary of the burden, effectiveness and safety of influenza vaccines in different populations.

Population	Burden of influenza	Influenza vaccine effectiveness	Influenza vaccine safety
Elderly	• Influenza disproportionately burdens the elderly • The risk of hospitalization and rates of emergency department and intensive care unit attendance and fatal hospitalization cases are highest among the elderly • Influenza outbreaks in aged-care facilities are an important contributor to the increased hospitalization and mortality observed in the elderly	• Vaccine effectiveness is lower in the elderly compared with working-age adults • This reduced effectiveness is often attributed to immunosenescence, however there is increasing evidence to suggest it may be associated with immunological responses to repeated vaccination • To overcome issues of immunogenicity and effectiveness, enhanced vaccines (e.g. adjuvanted and high-dose vaccines) are increasingly being recommended for use in elderly populations	• While influenza vaccines are reactogenic among the elderly, serious adverse events are rare • There is no evidence to suggest an increased risk of adverse events with the use of adjuvanted or high-dose vaccines
Paediatric	• Children are believed to have the highest rates of infection and complications arising from influenza • Their increased susceptibility to infection is believed to drive influenza epidemics, so vaccination of children has been proposed as a method of preventing transmission of influenza to other vulnerable groups	• Both IIV and LAIV formulations of influenza vaccine are available for paediatric use • Superior efficacy of LAIV compared with IIV demonstrated in randomized controlled trials led to its preferential recommendation in some countries • However, observational data have provided mixed evidence for the relative effectiveness of LAIV over IIV, so the recommendation for its use continues to be debated • Adjuvanted vaccines may be more effective in very young children	• Both IIV and LAIV vaccines are generally well tolerated in children • IIVs may cause pain, redness and swelling at the injection site, while LAIV is contraindicated in immunosuppressed individuals and their close contacts • Serious adverse events were reported for two vaccines in 2010, highlighting the need for ongoing post-licensure monitoring of vaccine safety
Pregnant	• Pregnant women are at higher risk of severe complications following influenza infection • However, there is limited evidence regarding the burden of influenza among pregnant women • The World Health Organization has recommended that pregnant women be made the highest priority group when considering expansion of national influenza vaccination programmes	• Clinical trials and observational studies have demonstrated that IIV is immunogenic and effective in pregnant women • Maternal antibodies elicited by IIV confer clinical protection to the infant against influenza	• Multiple studies have shown that influenza vaccination does not increase risk of pregnancy complications or adverse foetal outcomes • While the evidence is sparser, administration of IIV in early pregnancy is not associated with increased risk of congenital anomalies or spontaneous abortion

IIV, inactivated influenza vaccine; LAIV, live-attenuated influenza vaccine.

Elderly

Burden of influenza among the elderly

A recent review identified that influenza disproportionately burdens the elderly, with the risk of death nearly doubled in those aged 75 years or over compared with those aged 65–74 years.¹³ However, in many instances influenza is not recognized as an underlying cause of death. Ecological models have identified influenza-associated excess mortality in elderly persons related to a range of other chronic health conditions, including cardiovascular causes, diabetes, neoplasms and renal disease.^14–17 These risks extend to increased risk of hospitalization, with elderly adults accounting for more than half of hospital separations in a number of countries,^17–21 the highest rate of emergency department and intensive care unit (ICU) attendance,^22,23 and the highest rate of fatal hospitalization cases.²² Secondary bacterial infections post-influenza infection account for 75% of cases that present as severe pneumonia.²⁴ The economic costs for the health system and society for these hospitalizations are significant.²⁵ For the frail elderly who survive an influenza infection, illness can trigger a cascade of health problems, ultimately leading to loss of independence, which imposes further costs on society.²⁶

Influenza outbreaks in aged-care facilities (ACFs) represent an important contributor to the disproportionate hospitalization and mortality burden suffered in this age group. Attack rates of 20–40% have been reported from ACF influenza outbreaks.^27,28 Moreover, a review of published infectious disease outbreaks in ACFs observed a median case-fatality rate of 6.5% for influenza outbreaks and found influenza to be the most common cause of ACF outbreaks among 37 pathogens studied.²⁹ As the populations in most countries continue to age and demand for ACFs grows, the importance of outbreaks in ACFs will also continue to rise. Surveillance for respiratory infections is recommended by various national and international public health bodies and would inform outbreak management.^30–34 Similarly, influenza vaccination policies for residents and staff at ACFs exist in some countries^31,33,34 and have been endorsed by WHO.^31,33–35

Efficacy/effectiveness of influenza vaccines for the elderly

WHO recommends annual influenza vaccination for the prevention of influenza in the elderly aged 65 years and older.³⁶ The immune response to vaccination among elderly persons is reduced compared with younger adults, which can influence the efficacy of vaccines in this population.³⁷ A systematic review of test-negative studies published in 2016 reported lower pooled VE estimates against influenza A viruses for older adults (>60 years) compared with working-age adults (20–64 years), but not for influenza B viruses.³⁸ An updated review published in 2017 confirmed these findings with a pooled VE against any type of influenza of 51% (95% confidence interval [CI]: 45– 58) for working-age adults and 37% (95% CI: 30–44) for older adults.³⁹ How well the vaccine protects the elderly is probably associated with antigenic match between the vaccine and circulating viruses. In an earlier 2014 review VE among elderly persons was 41–61% during epidemic periods when the vaccine antigens match circulating viruses, but reduced to an average of 22–48% when the vaccine is not well matched.⁴⁰

There have been a number of issues which may influence VE among the elderly. Recently, identification of a representative A(H3N2) candidate vaccine virus has been hindered by its tendency to acquire adaptations in ovo that affect antigenicity,^41,42 as well as a greater diversity of viruses. This is particularly problematic for the elderly who are more vulnerable to severe consequences of A(H3N2) infection.⁴³ Moreover, there is emerging evidence that repeat annual vaccination may reduce VE, a phenomenon that is most often apparent for the A(H3N2) viruses.⁴⁴ These problems are particularly pertinent to the elderly, who are a highly vaccinated group. Whereas low effectiveness of influenza vaccine among the elderly has commonly been attributed to immunosenescence,⁴⁵ recent evidence suggests it may be associated with immunological responses to repeated vaccination.⁴⁶

Enhanced vaccines for the elderly

Enhanced vaccines, including adjuvanted and high-dose vaccines, may provide better immunogenicity and effectiveness for elderly adults and overcome some of the limitations of influenza vaccines for this age group. These vaccines are being used increasingly in the elderly populations, although paediatric uses have been considered.⁴⁷ Indeed, at the time of writing, Australia had just replaced standard-dose vaccines with high-dose and adjuvanted formulations for the elderly in their national immunization programme,⁴² and the UK and Canada were investigating the preferential use of enhanced vaccines for the elderly.^43,44

Adjuvanted vaccines contain compounds designed to boost the immune response to vaccination. Immunogenicity studies of adjuvanted vaccine indicate higher geometric mean titres (GMTs), seropositivity and seroconversion compared with standard-dose vaccines. However, the evidence for the efficacy and effectiveness of MF59 adjuvanted vaccines is weaker. A 2017 review of these vaccines⁴⁸ identified just one paper that compared the efficacy of adjuvanted vaccine with standard-dose vaccine and reported a relative VE comparing MF59-adjuvanted vaccine with standard trivalent influenza vaccine (TIV) of 63% (95% CI: 4–86%).⁴⁹ While at first this appears promising, this study had several limitations, with few observations, questionable selection criteria and an extraordinarily low standard-dose VE.⁴⁹ A few studies also exist comparing AS03 TIV with standard-dose TIV. In one study⁵⁰ AS03 was found to have a relative efficacy of 29% (95% CI: 7.6–46%) against severe influenza, which is similar to the improvement in VE observed for high-dose vaccines.

High-dose vaccines are named thus because they contain a higher concentration of antigen compared with standard-dose vaccines. For example, while standard-dose vaccines typically contain 15 μg of antigen, the high-dose Sanofi product Fluzone® contains four times this amount of antigen. The immunogenicity of this product in terms of seroconversion,^51,52 seropositivity^51,53 and GMTs^51–56 has been demonstrated to be higher compared with standard-dose vaccines. Its efficacy has also been assessed in a very large RCT, which identified that high-dose vaccine was 24% more effective than standard-dose vaccines.⁵⁷ Observational studies using US Medicare data also suggest that high-dose vaccine may be more effective than standard-dose vaccines for the prevention of hospitalization⁵⁸ and death.⁵⁹ Although these studies used nonspecific outcomes (clinical diagnosis +/– prescription for antiviral medication), their relative VE estimate was similar to the clinical trials, at around 22–24%. Furthermore, the relative effectiveness is speculated to be better in seasons when A(H3N2) circulates, which is important because this virus subtype is thought to cause the most influenza-associated deaths.⁴³ However, this relative improvement in VE may not necessarily translate to meaningful improvement in disease prevention in years where standard-dose vaccines perform poorly. It remains unclear whether the relative effectiveness of high-dose vaccine remains constant as the standard-dose VE changes. If constant, when the standard-dose vaccine provides VE of 50%, the absolute effectiveness of high-dose vaccine could be expected to be around 62%. However, if the standard-dose estimate was only 10%, which was the interim VE estimate for influenza A(H3N2) for 2017 in Australia,¹¹ VE for high-dose vaccines would only be expected to be around 12%.

Vaccination of ACF staff to protect elderly residents

In addition to immunizing the elderly, immunization of ACF staff is recommended in a number of countries.^31,33,34 This strategy aims to not only protect staff from infection, but also residents by way of herd immunity. However, no high-quality study has demonstrated that vaccinating staff reduces the risk of laboratory-confirmed influenza infection among residents.⁶⁰ A systematic review of studies that assessed the benefits of staff vaccination for residents of ACFs or patients in hospitals identified eight studies.⁶¹ Four cluster randomized trials conducted in ACFs reported a significant reduced risk of mortality (pooled estimate 42%; 95% CI: 15–41%)^62–65 and three trials observed reduced risk of acute respiratory infections (pooled estimate 29%; 95% CI: 15–41%)^62,64,65 among ACF residents. However, the quality of these trials, as assessed by GRADE criteria, was low to moderate.⁶¹ The outcomes were nonspecific (e.g. deaths meant all-cause mortality, not laboratory-confirmed influenza deaths), which has been demonstrated to provide biased VE estimates,⁶⁰ and a later review concluded that the reported estimates were likely to be highly biased.⁶⁶

Safety of influenza vaccines for the elderly

Although influenza vaccines are known to be reactogenic among the elderly, that is, causing localized and mild reactions, severe adverse events are rare. Enhanced vaccines have been associated with increased reactogenicity compared with standard-dose or other types of vaccines, but not increased risk of serious adverse events. A meta-analysis of 29 studies suggested no significant increased risk of serious adverse events for three classes of adjuvanted vaccine (AS01/AS02, AS03 and MF59) compared with control vaccines.⁶⁷ On the other hand, adjuvanted vaccines were more reactogenic: AS01/AS02-adjuvanted vaccines were associated with more drowsiness, irritability and loss of appetite; AS03-adjuvanted vaccines were associated with more local pain, swelling, fever and irritability; MF59-adjuvanted vaccines were associated with more local pain, redness, fever, irritability and loss of appetite. Fewer publications report on the safety of high-dose vaccines among the elderly. However, a review of seven studies of high-dose vaccines suggested no overall increased risk of serious adverse events associated with high-dose vaccines compared with standard-dose vaccines.⁶⁸

Children

Burden of influenza among children

Children are believed to have the highest rates of infection and complications arising from influenza. A systematic review estimated that in 2008 there were 49–162 million new cases of influenza and 28,000–111,500 influenza-associated deaths in children younger than 5 years of age.⁶⁹ Associated with this are high rates of excess outpatient visits, hospital admissions and antibiotic prescriptions.^70–74 Bacterial and other complications of influenza are frequent, especially in children less than 3 years of age. The burden of influenza-attributable mortality in young children is being increasingly recognized,^75–82 and may contribute to sudden infant deaths.^83,84 This all comes at significant cost to the health system.^{72,76,85–87} This burden is even greater among children with chronic medical conditions, such as asthma, heart disease and other chronic conditions. There are also considerable indirect costs of influenza infection among children, such as productivity losses among parents and caregivers.⁷²

Although vaccination of children to prevent infection is recommended, childhood vaccination has also been proposed as a method of preventing transmission of influenza to other vulnerable groups, such as the elderly.¹² Several studies have suggested that infections among children drive influenza epidemics due to their increased susceptibility to infection and greater contribution to the spread of virus among the population.^88–90

Efficacy and effectiveness of influenza vaccines for children

In most countries, paediatric formulations of inactivated influenza vaccine (IIV), which have reduced concentration of each antigen, are available for use among children aged at least 6 months. Both inactivated and live-attenuated formulations of influenza vaccines (LAIVs) are available, although the use of these vaccines varies by country. For children receiving their first dose of influenza vaccine, two doses are recommended at least 1 month apart in order to ensure adequate protection. The first dose primes the immune system and the second dose ensures protection through the influenza season. Children who are ‘partially’ vaccinated because they have received only one dose, may not be protected against influenza.^91,92

A recent update to a Cochrane systematic review confirmed that IIVs had 59% efficacy in preventing laboratory-confirmed influenza (95% CI: 41–71%) and 36% effectiveness in preventing influenza-like illness (95% CI: 24–46%) in healthy children aged 2–16 years.⁹³ This review found a lack of data about efficacy and effectiveness in children less than 2 years of age. However, this review did not consider the evidence from observational studies, which in recent years has drastically increased due to the widespread use of the test-negative design.⁹⁴ Both test-negative studies^95–97 and traditional observational study designs^98,99 have generally reported positive VE point estimates for IIVs for children younger than 2 years of age, but these studies have often been based on few cases and present wide CIs. For children less than 5 years of age, the evidence from observational studies is stronger, with reported estimates as high as 86% (95% CI: 29–97%).¹⁰⁰ It is unclear whether VE is likely to be better for older (2–5 years) or younger (< 2 years) children.^{95,96,98,100–102} In studies where VE is reported for both children and adults, however, the estimates for children are often higher.¹⁰³ The differences in VE among children and adults is likely to be affected by immune system responses associated with prior exposure to the vaccine and virus, which is currently poorly understood in children.^99–101

For children aged at least 2 years, LAIVs are available in some countries and are administered by nasal spray. Unlike the IIVs, LAIVs are able to stimulate innate immunity,^104,105 but do not stimulate a strong antibody response.¹⁰⁶ Although they are licensed for persons up to age 50 years in the USA, their effectiveness is believed to be inferior in older age groups.¹⁰⁷ Several RCTs have demonstrated superior efficacy of the LAIV compared with IIV among children.¹⁰⁸ Observational data have provided mixed evidence for the relative effectiveness of LAIVs over IIVs, particularly in recent years.^{109–114,115}

LAIV was preferentially recommended for children by the US Advisory Committee on Immunization Practices (ACIP).¹¹⁴ However, data from the 2015–2016 influenza season, which reported very poor VE for children, prompted the removal of this preferential recommendation. Although the initial ACIP recommendation was based on a comprehensive review of existing evidence,¹¹⁶ all available estimates were based on trivalent formulations. Since 2014, LAIV has had a quadrivalent formulation and competition among the influenza B lineages has been postulated to have reduced subsequent VE.¹¹⁶ Moreover, the VE for the A(H1N1)pdm09 component has been poor for several years and might be explained by reduced replicative fitness of the A(H1N1)pdm09 strains included in the vaccine, which may in turn have resulted in viral interference. In addition, some have queried whether repeated vaccination may have contributed to the attenuated effectiveness seen in the recent US studies, since attenuated effectiveness has not been seen in Europe, where LAIV has been available for fewer years.^117,118 However, preliminary studies in Finland¹¹¹ and the USA¹¹⁹ reported no statistically significant association between repeated vaccination and LAIV VE, although both studies were limited by low case numbers.¹¹⁹

In 2018, the ACIP re-reviewed available evidence for LAIV and found it to be similar in effectiveness to IIV against A(H3N2) viruses and generally effective against influenza B viruses, but limited in effectiveness against A(H1N1)pdm09-like viruses.¹²⁰ Since this review, the A(H1N1)pdm09 vaccine component has been updated to A/Slovenia/2903/2015. Data provided by the manufacturer suggest it elicits significantly higher antibody titres than the previous A(H1N1)pdm09 component and comparable seroconversion rates to A(H1N1) seasonal strains that were considered effective.¹²¹ However, there are currently no effectiveness estimates available for the newly formulated vaccine. This reformulation led to the ACIP reinstating its recommendation for LAIV use for the 2018–2019 influenza season, although with no preference over IIV.¹²¹

Adjuvanted formulations have also been developed for children. The rationale is that children respond poorly to standard influenza vaccines while adjuvants may elicit a more robust and persistent response.⁴⁷ Therefore, adjuvants will probably be most useful in very young children who are both vaccine and infection naïve. Studies have shown that MF59 vaccines may be more immunogenic and efficacious than standard vaccines, particularly in very young children aged 6–24 months; however, the benefits are inconsistent across subtypes and lineages.^122–124 Few data on effectiveness exist, except from the 2009 A(H1N1)pdm09 pandemic, which suggested low VE. ^125,126 In contrast, the AS03 monovalent A(H1N1)pdm09 vaccine was observed to have good VE for children that was superior to standard vaccines.^47,127 However, these benefits were overshadowed by safety concerns (see next section).

Safety of influenza vaccines for children

In general, studies indicate that influenza vaccines are well tolerated by children. For example, in a large population-based study of children aged 6–23 months the risk of medically attended AEFI was not statistically significant.¹²⁸ Active vaccine safety surveillance in Australia has shown that less than 5% of children experience a febrile adverse event following IIV immunization, and events requiring medical attention are uncommon.¹²⁹ IIVs may be more likely to cause pain, redness and swelling at the injection site, which are not a concern for LAIVs,¹³⁰ while LAIV is contraindicated in immunosuppressed individuals and their close contacts. Although adjuvanted vaccines are not widely available for children, safety data from clinical trials of adjuvanted influenza vaccines suggest no apparent safety concerns.¹³¹

While influenza vaccines are generally well tolerated in children, in 2010, two vaccines were associated with increased risk of severe adverse events. In Finland, AS03 adjuvanted A(H1N1)pdm09 Pandemrix® vaccine was found to contribute to the onset of narcolepsy in children aged 4–19 years,¹³² an observation that was later reported elsewhere in Europe.^133–135 It was hypothesized that it resulted from differences in antibody binding that were associated with particular genetic signatures common among northern Europeans and identified in affected children.^136,137 The event resulted in delicensing of AS03 for children younger than 20 years in Europe. In Australia, vaccination of children less than 5 years of age was suspended after an increase in emergency department presentations for febrile convulsions after vaccination.¹³⁸ It was thought to be associated with manufacturing processes that enhanced immune responses to vaccination and may have been peculiar to the new viral strains included in that year’s vaccine.^139,140 The event resulted in the removal of BioCSL’s licence to use Fluvax® in children aged less than 5 years.¹⁴¹ These two incidents highlight the limitations of clinical trials, which are typically underpowered to detect infrequent (1 per million) events, and the crucial role of implementing appropriate postmarketing surveillance of vaccine safety.¹⁴²

Pregnant women

Burden

Pregnant women are considered to be at higher risk of severe complications following influenza infection.¹⁴³ Based on evidence documenting this increased risk of severe disease among pregnant women,¹⁴³ the safety of vaccination during pregnancy,¹⁴⁴ and the effectiveness in preventing disease in pregnant women and their infants in the first 6 months,¹⁴⁵ the WHO Strategic Advisory Group of Experts has recommended that pregnant women be the highest priority group for countries initiating or expanding seasonal influenza vaccination programmes.¹⁴⁶ More than 44% of WHO member states have policies which recommend routine administration of IIV for pregnant women.¹⁴⁷ However, the recommended gestational timing of vaccination varies by country, and in some nations influenza vaccine continues to be listed as a contraindicated medication for pregnant women.

Few studies have comprehensively documented the burden of seasonal influenza among pregnant women, particularly in low- and middle-income countries.^148,149 However, existing epidemiological studies have consistently shown the risk of severe infection is greater among pregnant women compared with nonpregnant women.^143,150,151 Several studies have shown mortality associated with seasonal influenza may be greater during pregnancy¹⁵² and increased maternal and foetal mortality was documented during the 2009 H1N1 pandemic.^153–155 Although it is well accepted that pregnancy is associated with increased risk of hospitalization with influenza, results from studies describing the risk of mortality and ICU admission due to influenza among pregnant women are highly heterogeneous, and the potential risk of these outcomes among pregnant women remains uncertain.¹⁴³

Efficacy/effectiveness of influenza vaccines for pregnant women

In many countries, IIV is recommended for women who will be pregnant during the influenza season. LAIVs, as well as other live-attenuated vaccines, are contraindicated during pregnancy due to the hypothetical risk of transmission to the foetus. More recently, ACIP expanded their recommendation for influenza vaccines for adults to include recombinant influenza vaccines, which may be administered during pregnancy.¹⁵⁶

A range of clinical trials and observational studies have shown IIV is immunogenic in pregnant women.^157,158 Two clinical trials observed a 6–10-fold increase in GMTs among mothers who received IIVs, and more than 72% seroconversion was observed.¹⁵⁸ However, these trials also found that certain factors, such as immune impairment with HIV, may impede the maternal response to vaccination.¹⁵⁸ Although GMTs were lower, the estimated efficacy of IIV in these trials was similar for HIV-infected and uninfected women. Several additional clinical trials in low- and middle-income countries have suggested the efficacy of IIV is 50–70% in preventing laboratory-confirmed influenza in pregnant women.¹⁵⁹ Observational studies have similarly estimated that IIV is 44–65% effective against influenza among pregnant women.^160,161 There is, however, limited evidence demonstrating the effectiveness of influenza vaccine against severe influenza (i.e. infection requiring hospitalization) among pregnant women. This is likely due to the low incidence of influenza infection and small numbers of hospitalized women within each influenza season, making it difficult to estimate reliably IIV effectiveness against hospitalized disease among pregnant women.

Maternal antibodies produced in response to IIV cross the placenta and can offer protection to the infant through to 6 months of age; since infants less than 6 months of age cannot receive IIV, vaccination during pregnancy offers the best method of protection.¹⁵⁹ Although antibody transfer occurs most efficiently in the third trimester of pregnancy,¹⁶² a recent clinical trial in Nepal showed there was no difference in maternal seroconversion or infant:mother ratio of antibodies based on gestational timing of vaccination.¹⁶³

Maternal antibodies have been shown to confer clinical protection against laboratory-confirmed influenza in infants. Three recent clinical trials in Nepal, Mali and South Africa documented 30–63% efficacy in preventing laboratory-confirmed influenza in infants less than 6 months of age.¹⁵⁹ In high-income countries, a number of observational studies have been used to estimate VE. A UK study in 2013–2014 suggested that IIV in pregnancy was 71% effective (95% CI: 24–89%) in preventing influenza infection and 64% effective (95% CI: 6–86%) in preventing influenza hospitalization.¹⁶⁴ A US case-control study suggested IIV in pregnancy was 91% effective (95% CI: 62–98%) in preventing influenza hospitalization; however, the selection of controls in this study may have inflated this estimate.¹⁶⁵

Safety of influenza vaccines for pregnant women

A large number of post-licensure vaccine safety studies have demonstrated that influenza immunization during pregnancy is safe for both mother and infant. Studies over the past decade have shown that there is no increase in the risk of pregnancy complications, including pre-eclampsia and chorioamnionitis,^144,166,167 or adverse foetal outcomes, including stillbirth, preterm birth and foetal growth restriction.^144,168,169 However, the majority of these studies have been restricted to cohorts of pregnant women immunized in the second or third trimester. Although less frequently investigated, several studies have shown that administration of IIV in early pregnancy is not associated with an increased risk of congenital anomalies or spontaneous abortion.¹⁴⁴ However, one recent case-control study reported an increase in the risk of spontaneous abortion associated with IIV,¹⁷⁰ and although this study had methodological shortcomings,^171–173 it has stimulated additional review of the safety of IIV administration in early pregnancy.

Several studies, including recent clinical trials, have suggested IIV during pregnancy may be associated with improved health at birth.¹⁷⁴ For example, clinical trials in Bangladesh and Nepal showed that influenza immunization during pregnancy reduced the occurrence of low birthweight births.¹⁷⁵ However, results in this area have been extremely heterogeneous,¹⁷⁶ and several methodological issues in assessing potential foetal benefits of influenza vaccination during pregnancy have been raised in these findings.¹⁷⁷

Conclusion

Key populations targeted by vaccination programmes in many countries include elderly adults, children and pregnant women. While evidence exists to support these policies, ongoing surveillance and evaluation of influenza vaccines are necessary, both because changes to the vaccine formulation can shift the safety and effectiveness profile, and to increase the wealth of evidence. In particular, studies among children and pregnant women currently suffer from small sample problems and will benefit from the pooling of data across studies, for example through meta-analysis, to generate summary estimates and to better understand sources of heterogeneity.

Footnotes

Funding

The WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

ORCID iD

Sheena G. Sullivan

References

Nichol

KL.

Cost-effectiveness and socio-economic aspects of childhood influenza vaccination. Vaccine 2011; 29: 7554–7558.

Savidan

Chevat

Marsh

Economic evidence of influenza vaccination in children. Health Policy 2008; 86: 142–152.

Barr

McCauley

Cox

et al . Epidemiological, antigenic and genetic characteristics of seasonal influenza A(H1N1), A(H3N2) and B influenza viruses: basis for the WHO recommendation on the composition of influenza vaccines for use in the 2009–2010 Northern Hemisphere season. Vaccine 2009; 28: 1156–1167.

Kelly

Barr

Large trials confirm immunogenicity of H1N1 vaccines. Lancet 2009; 375: 6–9.

Last

Porta

A dictionary of epidemiology. 5th ed. New York: Oxford University Press, 2008.

Valenciano

Kissling

Cohen

et al . Estimates of pandemic influenza vaccine effectiveness in Europe, 2009–2010: results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) multicentre case-control study. PLoS Med 2010; 8: e1000388.

Castilla

Navascues

Casado

et al . Interim effectiveness of trivalent influenza vaccine in a season dominated by lineage mismatched influenza B, northern Spain, 2017/18. Euro Surveill 2018; 23: 18-00057.

Pebody

Warburton

Ellis

et al . End-of-season influenza vaccine effectiveness in adults and children, United Kingdom, 2016/17. Euro Surveill 2017; 22: 17-00306.

Flannery

Chung

Belongia

et al . Interim estimates of 2017–18 seasonal influenza vaccine effectiveness – United States, February 2018. Am J Transplant 2018; 18: 1020–1025.

10.

Skowronski

Chambers

De Serres

et al . Early season co-circulation of influenza A(H3N2) and B(Yamagata): interim estimates of 2017/18 vaccine effectiveness, Canada, January 2018. Euro Surveill 2018; 23: 18-00035.

11.

Sullivan

Chilver

Carville

et al . Low interim influenza vaccine effectiveness, Australia, 1 May to 24 September 2017. Euro Surveill 2017; 22: 17-00707.

12.

Baguelin

Flasche

Camacho

et al . Assessing optimal target populations for influenza vaccination programmes: an evidence synthesis and modelling study. PLoS Med 2013; 10: e1001527.

13.

Iuliano

Roguski

Chang

et al . Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet 2017; 391: 1285–1300.

14.

Goldstein

et al . Excess mortality impact of two epidemics of pandemic influenza A(H1N1pdm09) virus in Hong Kong. Influenza Other Respir Viruses 2014; 8: 1–7.

15.

World Health Organization. International meeting on influenza vaccine effectiveness, http://www.who.int/immunization/research/meetings_workshops/influenza_vaccine_effectiveness_dec12/en/ (2012, accessed 28 July 2014).

16.

Foppa

Cheng

Reynolds

et al . Deaths averted by influenza vaccination in the US during the seasons 2005/06 through 2013/14. Vaccine 2015; 33: 3003–3009.

17.

Newall

Wood

MacIntyre

CR.

Influenza-related hospitalisation and death in Australians aged 50 years and older. Vaccine 2008; 26: 2135–2141.

18.

Mitchell

Taylor

McGeer

et al . Understanding the burden of influenza infection among adults in Canadian hospitals: a comparison of the 2009–2010 pandemic season with the prepandemic and postpandemic seasons. Am J Infect Control 2013; 41: 1032–1037.

19.

Kusznierz

Carolina

Manuel

et al . Impact of influenza in the post-pandemic phase: clinical features in hospitalized patients with influenza A (H1N1) pdm09 and H3N2 viruses, during 2013 in Santa Fe, Argentina. J Med Virol 2017; 89: 1186–1191.

20.

Wong

Yang

Chan

et al . Influenza-associated hospitalization in a subtropical city. PLoS Med 2006; 3: e121.

21.

Mullooly

Bridges

Thompson

et al . Influenza- and RSV-associated hospitalizations among adults. Vaccine 2007; 25: 846–855.

22.

European Centre for Disease Prevention and Control. Risk assessment of seasonal influenza, EU/EEA, 2016–2017 – Update 25 Jan 2017, http://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/Risk-assessment-seasonal-influenza-2016-2017-update.pdf (2017, accessed 16 July 2018).

23.

Muscatello

Bein

Dinh

MM.

Emergency Department demand associated with seasonal influenza, 2010 through 2014, New South Wales, Australia. Western Pac Surveill Response J 2017; 8: 11–20.

24.

McElhaney

JE.

The unmet need in the elderly: designing new influenza vaccines for older adults. Vaccine 2005; 23: S10–S25.

25.

Peasah

Azziz-Baumgartner

Breese

et al . Influenza cost and cost-effectiveness studies globally – a review. Vaccine 2013; 31: 5339–5348.

26.

Gozalo

Pop-Vicas

Feng

et al . Effect of influenza on functional decline. J Am Geriatr Soc 2012; 60: 1260–1267.

27.

Booy

Lindley

Dwyer

et al . Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial. PLoS One 2012; 7: e46509.

28.

Gaillat

Chidiac

Fagnani

et al . Morbidity and mortality associated with influenza exposure in long-term care facilities for dependent elderly people. Eur J Clin Microbiol Infect Dis 2009; 28: 1077–1086.

29.

Utsumi

Makimoto

Quroshi

et al . Types of infectious outbreaks and their impact in elderly care facilities: a review of the literature. Age Ageing 2010; 39: 299–305.

30.

World Health Organization. Prevention and control of outbreaks of seasonal influenza in long-term care facilities: a review of the evidence and best-practice guidance. Copenhagen: WHO Regional Office for Europe, 2017.

31.

Centers for Disease Control and Prevention. Interim guidance for influenza outbreak management in long-term care facilities. Atlanta: Centers for Disease Control and Prevention, 2011.

32.

Public Health England. PHE guidelines on the management of outbreaks of influenza-like illness (ILI) in care homes, https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/747543/Influenza-like_illness_in_care_home_2018_FINAL.pdf (2017, accessed 17 July 2018).

33.

Communicable Diseases Network Australia. Guidelines for the prevention, control and public health management of influenza outbreaks in residential care facilities in Australia, https://www.health.gov.au/internet/main/publishing.nsf/Content/27BE697A7FBF5AB5CA257BF0001D3AC8/$File/RCF_Guidelines.pdf, 2017.

34.

Public Health Agency of Canada. Guidance: infection prevention and control measures for healthcare workers in acute care and long-term care settings: seasonal influenza, https://www.canada.ca/content/dam/phac-aspc/migration/phac-aspc/nois-sinp/guide/pdf/ac-sa-eng.pdf (2010, accessed 17 July 2018).

35.

World Health Organization. Strategy and action plan for healthy ageing in Europe, 2012–2020. Copenhagen: WHO Regional Office for Europe, 2012.

36.

Vaccines against influenza WHO position paper – November 2012. Wkly Epidemiol Rec 2012; 87: 461–476.

37.

Demicheli

Jefferson

Di Pietrantonj

et al . Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2018; 2: CD004876.

38.

Belongia

Simpson

King

et al . Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies. Lancet Infect Dis 2016; 16: 942–951.

39.

Rondy

El Omeiri

Thompson

et al . Effectiveness of influenza vaccines in preventing severe influenza illness among adults: a systematic review and meta-analysis of test-negative design case-control studies. J Infect 2017; 75: 381–394.

40.

Darvishian

Bijlsma

Hak

et al . Effectiveness of seasonal influenza vaccine in community-dwelling elderly people: a meta-analysis of test-negative design case-control studies. Lancet Infect Dis 2014; 14: 1228–1239.

41.

Zost

Parkhouse

Gumina

et al . Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci U S A 2017; 114: 12578–12583.

42.

Skowronski

Janjua

De Serres

et al . Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One 2014; 9: e92153.

43.

Vestergaard

Nielsen

Krause

et al . Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017. Euro Surveill 2017; 22: 30506.

44.

Belongia

Skowronski

McLean

et al . Repeated annual influenza vaccination and vaccine effectiveness: review of evidence. Expert Rev Vaccines 2017; 16: 1–14.

45.

Targonski

Jacobson

Poland

GA.

Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine 2007; 25: 3066–3069.

46.

Mosterin Hopping

McElhaney

Fonville

et al . The confounded effects of age and exposure history in response to influenza vaccination. Vaccine 2016; 34: 540–546.

47.

Wilkins

Kazmin

Napolitani

et al . AS03- and MF59-adjuvanted influenza vaccines in children. Front Immunol 2017; 8: 1760.

48.

Domnich

Arata

Amicizia

et al . Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: a systematic review and meta-analysis. Vaccine 2017; 35: 513–520.

49.

Van Buynder

Konrad

Van Buynder

et al . The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. Vaccine 2013; 31: 6122–6128.

50.

van Essen

Beran

Devaster

et al . Influenza symptoms and their impact on elderly adults: randomised trial of AS03-adjuvanted or non-adjuvanted inactivated trivalent seasonal influenza vaccines. Influenza Other Respir Viruses 2014; 8: 452–462.

51.

Falsey

Treanor

Tornieporth

et al . Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 2009; 200: 172–180.

52.

Couch

Winokur

Brady

et al . Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 2007; 25: 7656–7663.

53.

DiazGranados

Dunning

Kimmel

et al . Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014; 371: 635–645.

54.

DiazGranados

Dunning

Jordanov

et al . High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine 2013; 31: 861–866.

55.

Keitel

Atmar

Cate

et al . Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med 2006; 166: 1121–1127.

56.

Tsang

Gorse

Strout

et al . Immunogenicity and safety of Fluzone® intradermal and high-dose influenza vaccines in older adults ⩾ 65 years of age: a randomized, controlled, phase II trial. Vaccine 2014; 32: 2507–2517.

57.

DiazGranados

Dunning

Kimmel

et al . Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014; 371: 635–645.

58.

Izurieta

Thadani

Shay

et al . Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect Dis 2015; 15: 293–300.

59.

Shay

Chillarige

Kelman

et al . Comparative effectiveness of high-dose versus standard-dose influenza vaccines among us medicare beneficiaries in preventing postinfluenza deaths during 2012–2013 and 2013–2014. J Infect Dis 2017; 215: 510–517.

60.

Kelly

Letter to the editor: vaccinating healthcare workers: evidence and ethics. Euro Surveill 2015; 20: pii: 21006.

61.

Ahmed

Lindley

Allred

et al . Effect of influenza vaccination of healthcare personnel on morbidity and mortality among patients: systematic review and grading of evidence. Clin Infect Dis 2014; 58: 50–57.

62.

Potter

Stott

Roberts

et al . Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 1997; 175: 1–6.

63.

Carman

Elder

Wallace

et al . Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000; 355: 93–97.

64.

Hayward

Harling

Wetten

et al . Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial. BMJ 2006; 333: 1241.

65.

Lemaitre

Meret

Rothan-Tondeur

et al . Effect of influenza vaccination of nursing home staff on mortality of residents: a cluster-randomized trial. J Am Geriatr Soc 2009; 57: 1580–1586.

66.

De Serres

Skowronski

Ward

et al . Influenza vaccination of healthcare workers: critical analysis of the evidence for patient benefit underpinning policies of enforcement. PLoS One 2017; 12: e0163586.

67.

Baay

Bollaerts

Verstraeten

A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among older adults. Vaccine 2018; 36: 4207–4214.

68.

Wilkinson

Wei

Szwajcer

et al . Efficacy and safety of high-dose influenza vaccine in elderly adults: a systematic review and meta-analysis. Vaccine 2017; 35: 2775–2780.

69.

Nair

Brooks

Katz

et al . Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 2011; 378: 1917–1930.

70.

Heikkinen

Booy

Campins

et al . Should healthy children be vaccinated against influenza? A consensus report of the Summits of Independent European Vaccination Experts. Eur J Pediatr 2006; 165: 223–228.

71.

Neuzil

Mellen

Wright

et al . The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000; 342: 225–231.

72.

Poehling

Edwards

Weinberg

et al . The underrecognized burden of influenza in young children. N Engl J Med 2006; 355: 31–40.

73.

Neuzil

KM.

Influenza: new insights into an old disease. Curr Infect Dis Rep 2000; 2: 224–230.

74.

Brotherton

Wang

Schaffer

et al . Vaccine preventable diseases and vaccination coverage in Australia, 2003 to 2005. Commun Dis Intell 2007; 31(Suppl.): S1–S152.

75.

Centers for Disease Control and Prevention. Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza – Louisiana and Georgia, December 2006–January 2007. MMWR Morb Mortal Wkly Rep 2007; 56: 325–329.

76.

Bhat

Wright

Broder

et al . Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med 2005; 353: 2559–2567.

77.

Curson

McCracken

An Australian perspective of the 1918–1919 influenza pandemic. N S W Public Health Bull 2006; 17: 103–107.

78.

Dowell

Kupronis

Zell

et al . Mortality from pneumonia in children in the United States, 1939 through 1996. N Engl J Med 2000; 342: 1399–1407.

79.

Fleming

Pannell

Cross

KW.

Mortality in children from influenza and respiratory syncytial virus. J Epidemiol Community Health 2005; 59: 586–590.

80.

Moore

Vaudry

Scheifele

et al . Surveillance for influenza admissions among children hospitalized in Canadian immunization monitoring program active centers, 2003–2004. Pediatrics 2006; 118: e610–e619.

81.

Podewils

Liedtke

McDonald

et al . A national survey of severe influenza-associated complications among children and adults, 2003–2004. Clin Infect Dis 2005; 40: 1693–1696.

82.

van der Wouden

Bueving

Poole

et al . Influenza-associated deaths among children. N Engl J Med 2006; 354: 1317–1318; author reply: 8.

83.

Weber

Hartley

Ashworth

et al . Virological investigations in sudden unexpected deaths in infancy (SUDI). Forensic Sci Med Pathol 2010; 6: 261–267.

84.

Williams

Uren

Bretherton

Respiratory viruses and sudden infant death. Br Med J (Clin Res Ed) 1984; 288: 1491–1493.

85.

Ampofo

Gesteland

Bender

et al . Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics 2006; 118: 2409–2417.

86.

Grijalva

Weinberg

Bennett

et al . Estimating the undetected burden of influenza hospitalizations in children. Epidemiol Infect 2007; 135: 951–958.

87.

Zhang

et al . The epidemiology of hospitalized influenza in children, a two year population-based study in the People’s Republic of China. BMC Health Serv Res 2010; 10: 82.

88.

Longini

Jr Koopman

Monto

et al . Estimating household and community transmission parameters for influenza. Am J Epidemiol 1982; 115: 736–751.

89.

Schanzer

Vachon

Pelletier

Age-specific differences in influenza A epidemic curves: do children drive the spread of influenza epidemics?

Am J Epidemiol 2011; 174: 109–117.

90.

Viboud

Boelle

Cauchemez

et al . Risk factors of influenza transmission in households. Br J Gen Pract 2004; 54: 684–689.

91.

Shen

Campitelli

Calzavara

et al . Seasonal influenza vaccine effectiveness in pre- and full-term children aged 6–23 months over multiple seasons. Vaccine 2013; 31: 2974–2978.

92.

Staat

Griffin

Donauer

et al . Vaccine effectiveness for laboratory-confirmed influenza in children 6–59 months of age, 2005–2007. Vaccine 2011; 29: 9005–9011.

93.

Jefferson

Rivetti

Di Pietrantonj

et al . Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2018; 2: CD004879.

94.

Sullivan

Feng

Cowling

BJ.

Potential of the test-negative design for measuring influenza vaccine effectiveness: a systematic review. Expert Rev Vaccines 2014; 13: 1571–1591.

95.

Chiu

Kwan

MYW

Feng

et al . Influenza vaccine effectiveness against influenza A(H3N2) hospitalizations in children in Hong Kong in a prolonged season, 2016/2017. J Infect Dis 2018; 217: 1365–1371.

96.

Blyth

Jacoby

Effler

et al . Effectiveness of trivalent flu vaccine in healthy young children. Pediatrics 2014; 133: e1218–e1225.

97.

Shinjoh

Sugaya

Yamaguchi

et al . Effectiveness of trivalent inactivated influenza vaccine in children estimated by a test-negative case-control design study based on influenza rapid diagnostic test results. PLoS One 2015; 10: e0136539.

98.

Fujieda

Maeda

Kondo

et al . Inactivated influenza vaccine effectiveness in children under 6 years of age during the 2002–2003 season. Vaccine 2006; 24: 957–963.

99.

Maeda

Shintani

Nakano

et al . Failure of inactivated influenza A vaccine to protect healthy children aged 6–24 months. Pediatr Int 2004; 46: 122–125.

100.

Joshi

Iyer

St Sauver

et al . Effectiveness of inactivated influenza vaccine in children less than 5 years of age over multiple influenza seasons: a case-control study. Vaccine 2009; 27: 4457–4461.

101.

Shuler

Iwamoto

Bridges

et al . Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003–2004. Pediatrics 2007; 119: e587–e595.

102.

Sugaya

Shinjoh

Kawakami

et al . Trivalent inactivated influenza vaccine effective against influenza A(H3N2) variant viruses in children during the 2014/15 season, Japan. Euro Surveill 2016; 21: 30377.

103.

Osterholm

Kelley

Sommer

et al . Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 36–44.

104.

Kreijtz

Fouchier

Rimmelzwaan

GF.

Immune responses to influenza virus infection. Virus Res 2011; 162: 19–30.

105.

Oshansky

Thomas

PG.

The human side of influenza. J Leukoc Biol 2012; 92: 83–96.

106.

Khan

Polezhaev

Vasiljeva

et al . Comparison of US inactivated split-virus and Russian live attenuated, cold-adapted trivalent influenza vaccines in Russian schoolchildren. J Infect Dis 1996; 173: 453–456.

107.

Webster

Braciale

Monto

et al . Textbook of influenza. 2nd ed. Chichester, West Sussex; Hoboken, NJ: Wiley-Blackwell, 2013.

108.

Ambrose

Levin

Belshe

RB.

The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza Other Respir Viruses 2011; 5: 67–75.

109.

INFLUENZA in the United Kingdom, 1953–6; report to the Medical Research Council Committee on Clinical Trials of Influenza Vaccine by the Public Health Laboratory Service. Br Med J 1957; 2: 8–10.

110.

Pebody

Warburton

Ellis

et al . Effectiveness of seasonal influenza vaccine for adults and children in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2015/16 end-of-season results. Euro Surveill 2016; 21: 30348.

111.

Nohynek

Baum

Syrjanen

et al . Effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds – a nationwide cohort study Finland, influenza season 2015/16. Euro Surveill 2016; 21: 30346.

112.

Jackson

Chung

Jackson

et al . Influenza vaccine effectiveness in the United States during the 2015–2016 season. N Engl J Med 2017; 377: 534–543.

113.

Zimmerman

Nowalk

Chung

et al . 2014–2015 Influenza vaccine effectiveness in the United States by vaccine type. Clin Infect Dis 2016; 63: 1564–1573.

114.

Grohskopf

Olsen

Sokolow

et al . Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2014–15 influenza season. MMWR Morb Mortal Wkly Rep 2014; 63: 691–697.

115.

Ambrose

Bright

Mallory

Letter to the editor: potential causes of the decreased effectiveness of the influenza A(H1N1)pdm09 strain in live attenuated influenza vaccines. Euro Surveill 2016; 21: pii: 30394.

116.

Penttinen

Friede

MH.

Decreased effectiveness of the influenza A(H1N1)pdm09 strain in live attenuated influenza vaccines: an observational bias or a technical challenge?

Euro Surveill 2016; 21: 30350.

117.

Pebody

McMenamin

Nohynek

Live attenuated influenza vaccine (LAIV): recent effectiveness results from the USA and implications for LAIV programmes elsewhere. Arch Dis Child 2018; 103: 101–105.

118.

Grohskopf

LA.

Review of effectiveness of live attenuated influenza vaccine. Presented at the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) Meeting, 21 February 2018, Atlanta, GA.

119.

McLean

Caspard

Griffin

et al . Association of prior vaccination with influenza vaccine effectiveness in children receiving live attenuated or inactivated vaccine. JAMA Network Open 2018; 1: e183742.

120.

Grohskopf

Sokolow

Fry

et al . Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4) – United States, 2018–19 influenza season. MMWR Morb Mortal Wkly Rep 2018; 67: 643.

121.

Grohskopf

Sokolow

Fry

et al . Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4) – United States, 2018–19 influenza season. MMWR Morb Mortal Wkly Rep 2018; 67: 643–645.

122.

Vesikari

Kirstein

Devota Go

et al . Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial. Lancet Respir Med 2018; 6: 345–356.

123.

Vesikari

Knuf

Wutzler

et al . Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 2011; 365: 1406–1416.

124.

Sylvester

Study results of an adjuvanted quadravalent influenza vaccine in young children Meeting of the Advisory Committee on Immunization Practices (ACIP). Atlanta, Georgia: Centers for Disease Control and Prevention, 2018.

125.

Castilla

Moran

Martinez-Artola

et al . Effectiveness of the monovalent influenza A(H1N1)2009 vaccine in Navarre, Spain, 2009–2010: cohort and case-control study. Vaccine 2011; 29: 5919–5924.

126.

Wijnans

Dieleman

Voordouw

et al . Effectiveness of MF59 adjuvanted influenza A (H1N1) pdm09 vaccine in risk groups in the Netherlands. PLoS One 2013; 8: e63156.

127.

Lansbury

Smith

Beyer

et al . Effectiveness of 2009 pandemic influenza A(H1N1) vaccines: a systematic review and meta-analysis. Vaccine 2017; 35: 1996–2006.

128.

Hambidge

Glanz

France

et al . Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. JAMA 2006; 296: 1990–1997.

129.

Pillsbury

Cashman

Leeb

et al . Real-time safety surveillance of seasonal influenza vaccines in children, Australia, 2015. Euro Surveill 2015; 20: 30050.

130.

Belshe

Edwards

Vesikari

et al . Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 685–696.

131.

Stassijns

Bollaerts

Baay

et al . A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children. Vaccine 2016; 34: 714–722.

132.

Nohynek

Jokinen

Partinen

et al . AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One 2012; 7: e33536.

133.

Miller

Andrews

Stellitano

et al . Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346: f794.

134.

Winstone

Stellitano

Verity

et al . Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. Dev Med Child Neurol 2014; 56: 1117–1123.

135.

European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic influenza vaccination (a multi-country European epidemiological investigation). Stockholm: European Centre for Diseases Prevention and Control, 2012.

136.

Vaarala

Vuorela

Partinen

et al . Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. PLoS One 2014; 9: e114361.

137.

Sarkanen

Alakuijala

Julkunen

et al . Narcolepsy associated with pandemrix vaccine. Curr Neurol Neurosci Rep 2018; 18: 43.

138.

Kelly

Skowronski

De Serres

et al . Adverse events associated with 2010 CSL and other inactivated influenza vaccines. Med J Aust 2011; 195: 318–320.

139.

Rockman

Dyson

Koernig

et al . Evaluation of the bioactivity of influenza vaccine strains in vitro suggests that the introduction of new strains in the 2010 Southern Hemisphere trivalent influenza vaccine is associated with adverse events. Vaccine 2014; 32: 3861–3868.

140.

Rockman

Becher

Dyson

et al . Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine. Vaccine 2014; 32: 3869–3876.

141.

Therapeutic Goods Administration. Investigation into febrile reactions in young children following 2010 seasonal trivalent influenza vaccination: status report as at 2 July 2010 (updated 24 September 2010). Canberra: Therapeutic Goods Administration, 2010.

142.

Gold

Effler

Kelly

et al . Febrile convulsions after 2010 seasonal trivalent influenza vaccine: implications for vaccine safety surveillance in Australia. Med J Aust 2010; 193: 492–493.

143.

Mertz

Geraci

Winkup

et al . Pregnancy as a risk factor for severe outcomes from influenza virus infection: a systematic review and meta-analysis of observational studies. Vaccine 2017; 35: 521–528.

144.

Munoz

FM.

Safety of influenza vaccines in pregnant women. Am J Obstet Gynecol 2012; 207: S33–S37.

145.

Zaman

Roy

Arifeen

et al . Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med 2008; 359: 1555–1564.

146.

World Health Organization. Weekly Epidemiological Record, 2012, vol. 87, 21 [full issue]. Wkly Epidemiol Rec 2012; 87: 201–216.

147.

Ortiz

Perut

Dumolard

et al . A global review of national influenza immunization policies: analysis of the 2014 WHO/UNICEF Joint Reporting Form on immunization. Vaccine 2016; 34: 5400–5405.

148.

Bardají

Steinhoff

Macete

et al . The burden of vaccine-preventable diseases in pregnancy in low-resource settings. Lancet Glob Health 2016; 4: e152–e153.

149.

Katz

Gessner

Johnson

et al . Incidence of influenza virus infection among pregnant women: a systematic review. BMC Pregnancy Childbirth 2017; 17: 155.

150.

Ohfuji

Deguchi

Tachibana

et al . Estimating influenza disease burden among pregnant women: application of self-control method. Vaccine 2017; 35: 4811–4816.

151.

Dodds

McNeil

Fell

et al . Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ 2007; 176: 463–468.

152.

Tempia

Walaza

Cohen

et al . Mortality associated with seasonal and pandemic influenza among pregnant and nonpregnant women of childbearing age in a high-HIV-prevalence setting – South Africa, 1999–2009. Clin Infect Dis 2015; 61: 1063–1070.

153.

Centers for Disease Control and Prevention. Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1) – United States, April 2009–August 2010. MMWR Morb Mortal Wkly Rep 2011; 60: 1193–1196.

154.

Håberg

Trogstad

Gunnes

et al . Risk of fetal death after pandemic influenza virus infection or vaccination. N Engl J Med 2013; 368: 333–340.

155.

Barakat

Ihazmad

El Falaki

et al . 2009 Pandemic influenza A virus subtype H1N1 in Morocco, 2009–2010: epidemiology, transmissibility, and factors associated with fatal cases. J Infect Dis 2012; 206(Suppl. 1): S94–S100.

156.

Grohskopf

Sokolow

Broder

et al . Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices – United States, 2017–18 influenza season. Am J Transplant 2017; 17: 2970–2982.

157.

Steinhoff

Omer

Roy

et al . Influenza immunization in pregnancy – antibody responses in mothers and infants. N Engl J Med 2010; 362: 1644–1646.

158.

Madhi

Nunes

Cutland

CL.

Influenza vaccination of pregnant women and protection of their infants. N Engl J Med 2014; 371: 2340.

159.

Omer

SB.

Maternal immunization. N Engl J Med 2017; 376: 1256–1267.

160.

Regan

de Klerk

Moore

et al . Effectiveness of seasonal trivalent influenza vaccination against hospital-attended acute respiratory infections in pregnant women: a retrospective cohort study. Vaccine 2016; 34: 3649–3656.

161.

Thompson

Shifflett

et al . Effectiveness of seasonal trivalent influenza vaccine for preventing influenza virus illness among pregnant women: a population-based case-control study during the 2010–2011 and 2011–2012 influenza seasons. Clin Infect Dis 2014; 58: 449–457.

162.

Palmeira

Quinello

Silveira-Lessa

et al . IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol 2012; 2012: 985646.

163.

Katz

Englund

Steinhoff

et al . Impact of timing of influenza vaccination in pregnancy on transplacental antibody transfer, influenza incidence, and birth outcomes: a randomized trial in rural Nepal. Clin Infect Dis 2018; 67: 334–340.

164.

Dabrera

Zhao

Andrews

et al . Effectiveness of seasonal influenza vaccination during pregnancy in preventing influenza infection in infants, England, 2013/14. Euro Surveill 2014; 19: 20959.

165.

Benowitz

Esposito

Gracey

et al . Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants. Clin Infect Dis 2010; 51: 1355–1361.

166.

Black

Shinefield

France

et al . Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants. Am J Perinatol 2004; 21: 333–339.

167.

Naleway

Irving

Henninger

et al . Safety of influenza vaccination during pregnancy: a review of subsequent maternal obstetric events and findings from two recent cohort studies. Vaccine 2014; 32: 3122–3127.

168.

Nordin

Kharbanda

Benitez

et al . Maternal influenza vaccine and risks for preterm or small for gestational age birth. J Pediatr 2014; 164: 1051–1057. e2.

169.

Omer

Goodman

Steinhoff

et al . Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Med 2011; 8: e1000441.

170.

Donahue

Kieke

King

et al . Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010–11 and 2011–12. Vaccine 2017; 35: 5314–5322.

171.

Chambers

Mitchell

AA.

Commentary on: “Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010–11 and 2011–12”. Vaccine 2017; 35: 5323–5324.

172.

Ault

Riley

LE.

Response to Donahue et al. 2017 in press article. Vaccine 2018; 36: 2230.

173.

Regan

Moore

Sullivan

SG.

Does influenza vaccination during early pregnancy really increase the risk of miscarriage?

Vaccine 2018; 36: 2227.

174.

Savitz

Fell

Ortiz

et al . Does influenza vaccination improve pregnancy outcome? Methodological issues and research needs. Vaccine 2015; 33: 6430–6435.

175.

Steinhoff

Katz

Englund

et al . Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled trial. Lancet Infect Dis 2017; 17: 981–989.

176.

Fell

Platt

Lanes

et al . Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. BJOG 2015; 122: 17–26.

177.

Hutcheon

Fell

Jackson

et al . Detectable risks in studies of the fetal benefits of maternal influenza vaccination. Am J Epidemiol 2016; 184: 227–232.

Burden,effectiveness and safety of influenza vaccines in elderly,paediatric and pregnant populations

Abstract

Keywords

Introduction

Elderly

Burden of influenza among the elderly

Efficacy/effectiveness of influenza vaccines for the elderly

Enhanced vaccines for the elderly

Vaccination of ACF staff to protect elderly residents

Safety of influenza vaccines for the elderly

Children

Burden of influenza among children

Efficacy and effectiveness of influenza vaccines for children

Safety of influenza vaccines for children

Pregnant women

Burden

Efficacy/effectiveness of influenza vaccines for pregnant women

Safety of influenza vaccines for pregnant women

Conclusion

Footnotes

Funding

Conflict of interest statement

ORCID iD

References