Lithuanian University of Health Sciences Faculty of Medicine

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Lithuanian University of Health Sciences

Faculty of Medicine

Department of Infectious Diseases

Title of Master’s Thesis:

Influenza vaccine effectiveness in elderly during post-pandemic era

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree

Master of Medicine

Lithuanian University of Health Sciences

Author: Niklas Koschick

Supervisor: prof. dr. Auksė Mickienė

Kaunas 2018/2019

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8.4 Seasonal influenza vaccine effectiveness results for older adults in eight post-pandemic influenza seasons ... 19 8.4.1 2010/2011 season ... 22 8.4.2 2011/2012 season ... 23 8.4.3 2012/2013 season ... 24 8.4.4 2013/2014 season ... 25 8.4.5 2014/2015 season ... 26 8.4.6 2015/2016 season ... 27 8.4.7 2016/2017 season ... 28 8.4.8 2017/2018 season ... 29 9. Discussion ... 32 10. Conclusion ... 35 11. References ... 36 12. Annex No. 1 ... 44

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1. Summary

Author: Niklas Koschick

Title of research: Influenza vaccine effectiveness in elderly during post-pandemic era

Aim: To review seasonal influenza vaccine effectiveness against laboratory-confirmed influenza in older adults during post-pandemic era in Northern hemisphere (United States, Canada, and Europe) Objectives:

1. To describe influenza virus circulation in Northern hemisphere during 2010-2018

2. To characterize influenza vaccine composition during 2010-2018 and evaluate vaccine match/mismatch with the virus strains circulated

3. To analyze methods used for influenza vaccine effectiveness evaluations

4. To represent seasonal influenza vaccine effectiveness results for older adults in eight post-pandemic seasons

Methodology: This was a systemic literature review where searches were conducted using two databases: ScienceDirect and Medline (PubMed). All articles were included starting from the year 2011. The search terms used were: ‘’influenza vaccine effectiveness’’, ‘’older adults’’, ‘’elderly’’, and different countries (‘’Spain’’,’’USA’’,’’Canada’’,’’United Kingdom’’),’’IMove+’’. Searches were sorted by different post-pandemic seasons. Keywords were matched to database indexing terms.

Results: The results show that the influenza vaccine effectiveness is very volatile. The rise or fall of effectiveness is not related to a country. Over eight seasons the vaccine effectiveness had seasons were it was more protective (e.g. 2010/2011) and less protective (e.g. 2014/2015). There was no significant difference between studies including only outpatient, only hospital or mixed population. A decrease in vaccine effectiveness appeared when the predominantly circulating strain was not matching the corresponding strain in the vaccine.

Conclusions: The results establish a different geographical distribution of matches/mismatches and a connection between non-matching influenza seasons and diminished influenza vaccine effectiveness in older adults. The test-negative study design should be implemented for all further conducted influenza vaccine effectiveness studies as it shows a good validity combined with cheaper and easier adaptation compared to formerly used randomized controlled trials. The results furthermore suggest that during the last eight post-pandemic seasons the vaccination had relevant protective value in older adults. It supports the importance of thorough influenza surveillance to increase the rate of matching influenza strains.

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2. Acknowledgements

I would like to express my gratitude towards my supervisor prof. dr. Auksė Mickienė and Monika Kuliešė, MD and PhD student at the Infectious Diseases Department, who consulted me during preparation of my thesis. Their knowledge on the field of vaccination programs and effectiveness evaluation, as well as their work on various vaccine effectiveness studies provided a big help and supported me a lot throughout the process.

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3. Conflict of Interest

The author reports no conflict of interest.

4. Abbreviations

WHO- World Health Organization

ECDC- European Center of Disease Control CDC- Center of Disease Control

SIVE- seasonal Influenza Vaccine Effectiveness CI- confidence Interval

TND- test-negative design RCT- randomized controlled trial VE- vaccine effectiveness

aVE- adjusted vaccine effectiveness TIV- trivalent influenza vaccine ILI- influenza like illness ARI- acute respiratory infection

RT-PCR- reverse transcriptase polymerase chain reaction EU- European Union

EEA- European Economic Area HI- Hemagglutination Inhibition

I-MOVE+- Integrated Monitoring of Vaccines in Europe GMT- geometric mean titer

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5. Introduction

Older adults/elderly are mostly considered as persons over the age of 65 years. Mortality and morbidity are highly increased in older people. Estimates concerning older adult mortality indicate an highly increased mortality rate with increasing age (0.1 to 6.4 per 100 000 individuals for people younger than 65 years in contrast to 2.9 to 44.0 per 100 000 individuals for people aged between 65 and 74 years) [1]. The rise in mortality results from a higher rate of influenza associated complications. The most common complications manifest as primary influenza pneumonia, secondary bacterial pneumonia, rhabdomyolysis and rarely as central nervous system involvement. In most cases, the management of these influenza infection outcomes requires a long-term hospital stay and intensive treatment regimen.

The only preventive measure is an annual vaccination against the influenza virus. It does not only prevent influenza infections, but also prevents the progression of disease into severe stages in already infected persons [2].

The fact that the vaccination has to be redone every year is one of the reasons that the coverage of influenza vaccination does not reach the advised coverage goal. The ECDC committee has set a 75% influenza vaccination coverage goal, which has not been reached by any EU country during the last three seasons. Highest coverage rates among EU countries were found in States of the United Kingdom and the Netherlands, while the coverage rates in Poland, Latvia and Estonia were the lowest [3].

Fig 1. Coverage rates during three seasons in EU/EEA countries in comparison to the EU target [3]

Despite the current recommendations to vaccinate older adults it is important to evaluate how protective the vaccination is every year.

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6. Aim and Objectives

Aim: To review seasonal influenza vaccine effectiveness against laboratory-confirmed influenza in older adults in post-pandemic era in Northern hemisphere (United States, Canada, and Europe)

Objectives:

1. To describe influenza virus circulation in Northern hemisphere during 2010-2018

2. To characterize influenza vaccine composition during 2010-2018 and evaluate vaccine match/mismatch with the virus strains circulated

3. To analyze methods used for influenza vaccine effectiveness evaluations.

4. To present seasonal influenza vaccine effectiveness results for older adults in eight post-pandemic seasons

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7. Research methodology and methods

Methodology: This was a systemic literature review where searches were conducted using the databases ScienceDirect and Medline (PubMed). All articles were included starting from the year 2011. The search terms used were: ‘’influenza vaccine effectiveness’’, ‘’older adults’’, ‘’elderly’’, and different countries (‘’Spain’’,’’USA’’,’’Canada’’,’’United Kingdom’’),’’I-MOVE+’’(which is an initiative with a consortium of 26 partners across Europe with the goal to create a platform for standardized vaccine surveillance [35]). Searches were sorted by different post-pandemic seasons. Keywords were matched to database indexing terms.

Selection criteria: In most studies the term older adults was defined as people over the age of 65 (in a few studies people over the age of 50 years were included as it was in the study defined as elderly person). People in the studies were defined as vaccinated, if time between vaccination and influenza infection was at least 14 days. Studies, which represented a span of time longer than one influenza season between flu and previous vaccination, were excluded. . Influenza studies use different influenza definitions. The included studies either use ILI or SARI definitions. In contrast to ILI, SARI definition also includes hospitalization in its definition. The WHO recommends both definitions for usage in influenza surveillance. The definitions to do not aim to detect every single influenza case, but evaluate the pattern of influenza transmission and burden of disease.

Table 1. Number of scientific research papers on seasonal influenza vaccine effectiveness sorted by season

North America Europe

USA Canada IMove+ Spain United Kingdom 2010/2011 2 2 1 2 1 2011/2012 2 1 1 2 1 2012/2013 2 1 1 1 1 2013/2014 2 2 1 2 0 2014/2015 2 3 1 2 1 2015/2016 1 1 1 1 1 2016/2017 3 1 3 1 1 2017/2018 2 1 2 1 1

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The search was conducted with the upper mentioned criteria; studies were excluded if not matching the inclusion criteria or were not in alignment with this master thesis objectives.

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8. Results

8.1 Influenza Virus Circulation in Northern Hemisphere from 2010 to 2018

2010/2011 season

The season in North America was predominated by influenza A(H3N2). The influenza A(H3N2) virus was antigenically determined as A/Perth/16/2009-like. However, during this season a high number of influenza A(H1N1) and Influenza B viruses also circulated throughout the United States. The highest number of influenza cases were evident in early February with 36 % out of all influenza cases within this season. Canada showed a similar pattern: influenza A(H3N2) was the most common virus, antigenically characterized as A/Perth/16/2009-like. In contrast to the United States, other influenza subtypes were not as predominant as the H3N2 subtype. The virologic distribution showed a beginning influenza transmission in the provinces of Ontario and Quebec with a later distribution to the western provinces. In Europe, the predominating virus was influenza A(H1N1pdm09), which had the antigenic subgroup A/California/7/2009 in most cases. The seasonal peak in Europe appeared in late January to early February in western Europe and around two weeks later in eastern European countries as well [4].

2011/2012 season

Like the previous season, the United States had a predomination of influenza A(H3N2), with antigenic subtype A/Perth/16/2009. 73% of all subtyped influenza viruses belonged to the A(H3N2) subgroup and within this subgroup, 75% were antigenically classified as A/Perth/16/2009. The peak virus fluctuation in the USA appeared in the middle of March. The influenza season started late at the end of November. In Canada, there was co-fluctuation of all four influenza subtypes; however the predominating virus was influenza B. The peak transmission in Canada was from late March to early April. There were regional differences in virus predomination as in some provinces, e.g. Columbia and Alberta, influenza A virus occurrence was superior to influenza B. Across Europe, most of the cases were influenza A(H3N2) with 98% being classified as antigenic subtype A/Victoria/208/2009. Similar to the North American countries the influenza season started unusually late in the European region. The peak of influenza cases occurred in western Europe at the end of February/early March and slightly later in eastern European countries in April [5].

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In North America, in the United States as well as in Canada, influenza A(H3N2) was predominating across the season. The most common detected subtype was A/Victoria/361/2011-like. The season started in early November in both countries and had its peak around the mid of January. Even though influenza A(H3N2) was predominating by looking at the confirmed detections, both North American countries experienced a switch in virus predominance after the peak with a change from influenza A(H3N2) to influenza B [6]. In Europe as an entirety, influenza A(not subtyped) and influenza B (Yamagata lineage) B/Wisconsin/1/2010 were co-fluctuating. The reason for the high peak of not subtyped influenza A viruses is not identifiable. The season started in the end of November of 2012 and continued until mid-April of 2013. The influenza peak in Europe occurred around the beginning of February 2013. In comparison to the 2011/2012 season, this season was slightly longer [7]

2013/2014 season

The predominating strain for this season was the same for both North American countries with influenza A(H1N1) A/Victoria/361/2011.The season started in November with the first influenza detections. The peak was around the second week of January. This season had a similar pattern as the previous one with a switch after peak detections to influenza B. In the North American region, this season was the first one with influenza A(H1N1) predomination since the worldwide pandemic in 2009 [8].

In Europe, there was co-fluctuation of mostly two strains: influenza A(H1N1) A/California/7/2009 and influenza A(H3N2) A/Texas/50/2012. The first influenza detections in European countries began to increase in beginning of December in 2013 and peaked with 44% in the late January [9].

2014/2015 season

In the United States of America, the season was predominated by influenza A(H3N2) A/Switzerland/9715293/2013. The influenza detections started to increase in mid to late November and reached its peak during the last weeks of December. The same virus was also the most common in Canada, but most cases showed an insufficient titer to run a HI assay. The seasonal influenza detections increased at the mid of November and peaked in the end of December. As in the previous seasons, in late January the predominance of influenza viruses changed to influenza B in both North American countries [10]. Most cases in Europe were also influenza A(H3N2) ones, but with the antigenic subtype A/HongKong/5738/2014 being the dominant one. The European influenza season started in December 2014 by crossing the threshold of 10% and reached its maximum around February 2015 with 61% [11].

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In the USA this season was dominated mainly by a co-circulation between influenza A(H1N1) A/California/7/2009 and influenza B Yamagata Lineage (B/Phuket/3073/2013). The season in the United States peaked late, in the week ending at March 12. The lateness of this peak of influenza activity can be shown by the fact that during the last 18 seasons only three peaked in March (2015-2016, 2011-2012 and 2005-2006). Canada had a co-circulation between influenza A(H1N1) A/California/07/2009 and influenza B Victoria lineage (B/Brisbane/60/2008). The influenza peak in Canada was identical to the US peak during this season [12]. Europe showed a co-predominance of influenza A(H1N1) A/California/7/2009 and influenza B(Victoria lineage). In the mid of December 2015 the virus detection crossed the 10% threshold and therefore indicated the start of the European influenza season. With 60% the season reached its peak in March 2016. In some countries (e.g. Ireland, France and Spain) a co-circulation was evident, whereas in other countries either influenza A(H1N1) or influenza B (Victoria lineage) were more prominent [13].

2016/2017 season

This season was dominated by influenza A(H3N2) throughout the northern hemisphere. In the United States, the predominant strain was influenza A(H3N2) A/HongKong/4801/2014. The season began in the middle of December with the number of influenza detections crossing the baseline of 10%. The seasonal peak occurred in February. In Canada, the most common strain was influenza A(H3N2) A/Bolzano/7/2016. The Canadian season also started around the mid-December, but in contrast to the USA peaked in the mid of January already [14]. The European season started earlier than the North American one by passing the influenza detection threshold in the mid of November 2016.This was the earliest season start across Europe in the previous five years. The seasonal peak occurred between the end of December to the end of January. The predominating strain in Europe appeared to be influenza A(H3N2) with the A/Bolzano/7/2016 subtype [15].

2017/2018 season

In the USA, the season’s most common strain was influenza A(H3N2) A/HongKong/4802/2014. The influenza season started in mid-November with peaks from late January to early February. Canada showed a predomination of virus circulation of influenza A(H3N2) A/HongKong/4801/2014. The seasonal activity was similar to the influenza activity in the USA. It is important to mention that in both countries influenza B viruses also circulated at levels that were higher than usual [16]. Across most of the European countries, influenza B(Yamagata lineage) predominated over other influenza virus subtypes. The seasonal influenza detection crossed the 10% border at the middle of November

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and was therefore close to the beginning of the 2016/2017 season. The peak with over 60% of detections occurred during a long time span between end of December and beginning of January [17].

8.2 Influenza vaccine composition and it’s match/mismatch with circulating strains

Since the year 1973, the World Health Organization (WHO) provided recommendations on the composition of influenza vaccines. Since the year 1998 the recommendations are divided into Northern hemisphere and Southern hemisphere to have a correct timing for the start of the influenza season. The epidemiological and virological information about influenza viruses are assessed by the Global Influenza Surveillance Network (GISN). 121 National Influenza Centres (NICs) in 92 countries and 5 WHO Collaborating Centres (WHO CCs) comprise this network [18].

The analysis on match and mismatch between circulating strains and influenza vaccine will just include the trivalent influenza vaccine (TIV), which is free of charge for older adult persons in most countries [19]. The TIV always contains an influenza A(H1N1) strain, an influenza A(H3N2) strain and an influenza B strain (either Yamagata or Victoria lineage).

Information on predominating virus strains and WHO influenza vaccine composition recommendation can be found at Annex No.1 in the end of the master thesis.

The 2010/2011 influenza vaccine composition recommendation for the Northern hemisphere included an A/California/7/2009 (H1N1)-like virus; an A/Perth/16/2009 (H3N2)-like virus; a B/Brisbane/60/2008-like virus [20]. In the United States and Canada, the predominating Influenza A (H3N2) virus matched the subgroup of vaccine composition. The predominating influenza A(H1N1) subgroup in the observed European countries matched the vaccine composition strain as well. This concludes that every country included in this review experienced a match between circulating strain and vaccine components.

In the 2011/2012 influenza vaccine composition recommendation for the Northern hemisphere an A/California/7/2009 (H1N1)-like virus; an A/Perth/16/2009 (H3N2)-like virus; a B/Brisbane/60/2008-like virus were included [21]. The United States influenza A(H3N2) subtype matched this season’s vaccine composition. Since there was a fluctuation of all four influenza subtypes in Canada, one influenza B subtype was not included in the TIV. This non-matching subtype belonged to the

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Yamagata lineage (B/Wisconsin/01/2010). The other three subtypes in Canada matched the vaccine composition proposed by the WHO. The predominating European subtype influenza A(H3N2) A/Victoria/208/2009 did not match with the influenza A(H3N2) strain contained in the influenza vaccine (A/Perth/16/2009).

For the 2012/2013 season the WHO recommended an A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like virus; a B/Wisconsin/1/2010-like virus to be included in the vaccine composition [22]. The predominating influenza A(H3N2) subtype was identical in the USA and Canada and matched with the strain in this season’s influenza vaccine. In Europe influenza A and B were both circulating in similar numbers. The influenza A matching cannot be evaluated as most viruses were not classified in any of the subgroups. The predominating circulating influenza B strain was identical with the strain in the influenza vaccine recommendation.

In the 2013/2014 season the influenza vaccine recommendation included an A/California/7/2009 (H1N1)pdm09-like virus; an A(H3N2) virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011b; a B/Massachusetts/2/2012-like virus [23]. The dominating influenza A(H1N1) subtype circulating in the United States and Canada matched the recommendations of the vaccine composition by the WHO. Europe saw a circulation of both influenza A subtypes. Both influenza A subtypes circulating in Europe were matching the vaccine composition.

In the 2014/2015 season the World health organization recommended an A/California/7/2009 (H1N1)pdm09-like virus; an A/Texas/50/2012 (H3N2)-like virus; a B/Massachusetts/2/2012-like virus to be component of the influenza vaccine [24]. For both North American countries the season resulted in a mismatch with the vaccine components. The predominating influenza A(H3N2) was different from the suggested vaccine strain. The European influenza surveillance showed similarities to North America. Even tough another influenza A(H3N2) strain appeared in Europe, this strain was also antigenically different from the recommendations. This concludes that among all observed countries of the Northern hemisphere a mismatch with the vaccine components occurred.

The 2015/2016 vaccine composition recommendation included an A/California/7/2009 (H1N1)pdm09-like virus; an A/Switzerland/9715293/2013 (H3N2)-(H1N1)pdm09-like virus; a B/Phuket/3073/2013-(H1N1)pdm09-like virus [25]. The predominating co-circulating influenza A(H1N1) and influenza B(Yamagata lineage) strains in the United States were matching the suggested components of the vaccine. Canada experienced a co-circulation between influenza A(H1N1) and influenza B (Victoria lineage). The influenza A strain was identical to the vaccine’s strain, but the Victoria lineage of influenza B was not considered in the

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vaccine recommendation and resulted in a mismatch. In Europe, the state of match/mismatch was comparable to Canada as the same strains were co-circulating. Therefore, the influenza B(Victoria lineage) mismatched the influenza vaccine strain.

For 2016/2017 the WHO recommended the inclusion of an A/California/7/2009 (H1N1)pdm09-like virus; an A/Hong Kong/4801/2014 (H3N2)-like virus; a B/Brisbane/60/2008-like virus as components of the influenza vaccine [26]. The predominating influenza A(H3N2) strain in the United States showed a match with the corresponding vaccine strain for this season. In Canada and Europe the predominating influenza A(H3N2) A/Bolzano/7/2016 was antigenically different from the suggested influenza A(H3N2) an A/Hong Kong/4801/2014 strain and therefore a mismatch.

2017/2018 was characterized by a WHO recommendation for the influenza vaccine composition of an A/Michigan/45/2015 (H1N1)pdm09-like virus; an A/Hong Kong/4801/2014 (H3N2)-like virus; and a B/Brisbane/60/2008-like virus [27]. In both North American countries the predominating influenza A(H3N2) virus strain matched the WHO suggestion. The situation was different all over Europe: There was a huge predomination of influenza B(Yamagata) B/Phucket/3073/2013. The WHO recommendation did not contain a strain of the Yamagata lineage, only the Victoria lineage. This means mismatch occurred during this season between circulating strain and vaccine strain.

8.3 Methods used in influenza vaccine effectiveness evaluations

For a long period of time studies evaluated the influenza vaccine effectiveness by the use of a randomized controlled trial (RCT) or different kinds of case-control studies. The biggest problems were the high costs and the probable presence of bias. In the 2004/2005 season the Canadian influenza vaccine effectiveness estimation used a new study design named test-negative case-control (TND) for the first time. Since then all Canadian influenza vaccine effectiveness studies incorporated this design. After this design was proven valid European and US studies also started to use it to estimate vaccine effectiveness among the northern hemisphere.

The TND compares the vaccination status between influenza positive cases and influenza test-negative controls. The principle of this study design includes subjects that present to medical institutions (might be outpatient and/or inpatient presentation) during the influenza season with influenza-like illness (ILI) symptoms. The definition of ILI includes different parameters according to different organizations. The following are the three most common definitions. The WHO proposes a

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definition that includes an acute respiratory infection with: measured fever of ≥ 38 C°; cough and with onset within the last 10 days. The CDC defined an influenza-like illness as a patient having fever (temperature of 100°F/ 37.8°C or greater) and a cough and/or a sore throat in the absence of a known cause other than influenza.

The third definition was introduced by the European Center of Disease Control (ECDC) and includes a sudden onset of symptoms, at least one of the general symptoms (fever, feverishness, headache, malaise, myalgia) and at least one of the respiratory symptoms (cough, sore throat, shortness of breath). Different studies use different definitions of ILI, which may lead to an unequal recruitment of subjects. Therefore, possible influenza cases may be missed.

After the ILI presentation, the patients are tested for influenza positivity. Nasopharyngeal and/or throat swabs are taken and further processed by either viral culture or polymerase chain reaction (PCR). For a long time viral cultures were the gold standard in detecting influenza. Nowadays nearly all studies use the RT-PCR technique to assess influenza status. RT-PCR uses the amplification of viral DNA/RNA for the influenza detection. As the influenza virus is a RNA virus before the PCR, a reverse transcription has to be performed. The PCR technique has several advantages compared to the viral culture like consuming less time and having a high sensitivity and specificity. According to a research article by Talbot et al. studies using PCR as main diagnostic instrument have shown the sensitivity of culture to be 21-50% in older adults [28]. Another problem with viral cultures in older adults is that it generally relies on a higher value of viral load. Older adults usually exhibit a lower viral load than other age groups, which is another contributing factor to a possible decrease in viral culture sensitivity. Less often used influenza detection techniques are the rapid antigen testing and fluorescent antigen testing. The rapid antigen testing uses enzyme immunoassays and usually shows a result in less than 15 minutes. In older adults, the test has low sensitivity, but better specificities. That concludes that a positive test result has a high possibility of influenza infection, however a negative result does not rule out an infection. The fluorescent antigen testing uses a microscopic influenza detection by the use of specific viral fluorescent staining methods. Across all age groups, the sensitivity is 68% compared with viral culture.

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Fig. 2 Scheme of test-negative design in evaluating influenza vaccine effectiveness [29]

After the influenza detection and classification into influenza-positive cases and influenza-negative controls, cases and controls are afterwards compared to the assessed vaccination status. The assessment of vaccination status differs from study to study and involves a variety of modalities. Some studies use a face-to-face interview with the patient or a generalized questionnaire to get knowledge about the influenza vaccination status. As this self-reporting may be wrong in some cases (e.g. due to uncertainty of the patient) this can lead to misclassification of vaccination status. Another often-used method is the review of medical records to confirm the status of vaccination. This method has a higher validity because it is not relying on the patient’s opinion and memory and is therefore an objective assessment. Some countries/studies only include patients with vaccination status taken from a regional register. An example are influenza vaccine effectiveness studies from the region of Valencia, Spain: data is taken from the Valencia population-based Vaccine Information System. Medical records and the use of registries have more objective validity than a self-report assessment, which may contain certain biases.

The simplicity of the TND design raises the question about the validity and accuracy of it in determining the effectiveness of influenza vaccines. A North American study [30] compared the accuracy of TND case-control with the previous gold standard of randomized controlled trial design. Four datasets were analyzed (three were limited to children under the age of seven years and one to elderly over age of 65). I will just consider the elderly dataset [31] to be in alignment with the research objectives.

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The results showed that the point estimates and surrounding 95% Confidence Intervals were close to identical:

Table 2. Comparison of TND design vs. Classical RCT adapted from De Serres G et al [30]

Population Total Test-positive

for influenza Test-negative no censoring Test-negative with censoring No swab Number of LAIV 1620 71 944 894 655 Number of placebo 1622 125 981 892 605 Classical RCT TND no censoring TND with censoring Efficacy against influenza (95% CI) Not applicable 43.1 (23.3 to 58.1) 41.0 (20.0 to 56.5) 43.3 (23.1 to 58.3) Not applicable Efficacy against non-influenza (95% CI)

Not applicable Not applicable 1 (-5 to 7) 0 (-7 to 6) Not applicable

The graphic displays that the efficacy of influenza vaccine was 43.1 % in the classical RCT, 41.0 % in the TND no censoring and 43.3 % in the TND with censoring. The study concludes that there is no significant difference between RCT and TND in evaluating the influenza vaccine effectiveness/efficacy [30].

The TND was also developed to reduce substantial bias towards vaccine effectiveness estimation. Several studies examined if and how bias affects the validity of TND.

There are different forms of bias possibly affecting the estimation of vaccine effectiveness.

One study evaluated whether self-report of vaccination status may produce bias towards vaccine effectiveness. It states that self-reported vaccination rarely has a specificity higher than 90%. The study constructed a simulation in which a base vaccine effectiveness was confronted with different numbers of specificity and sensitivity. As an example, self-report values of 95% sensitivity and 90% specificity led to a mean vaccine effectiveness of 42%. In this simulated case, the true vaccine effectiveness was 50%, which meant that even with quite high specificity and sensitivity values the

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bias proportion was -0.16. The study changed the values of the true vaccine effectiveness during the simulation and similar results of bias proportion were shown [32]. This concludes self-report in TND studies confers a negative bias towards vaccine effectiveness.

Especially in older adults, frailty may influence the influenza vaccine effectiveness. Frailty is defined as a physiological decrease of functions in later life, characterized by marked vulnerability to adverse health outcomes [33]. A frail person is more prone to not receive the annual influenza vaccination and to experience an increasing number of hospitalizations. Different studies assessed that frail persons show lower influenza vaccine effectiveness compared to non-frail persons in classic case-controls and RCT’s. Does the test-negative design have the same limitation when confronted with frail persons? Talbot HK et al. conducted a study to demonstrate the effect of frailty on the VE in the test-negative design. Adults over the age of 50 years were enrolled during a five-year period (November 2006 to May 2012). The pandemic season 2010/2011 was excluded from the results. The authors used a modified Rockwood index, which includes 70 categories of medical and functional issues, to calculate frailty. Influenza vaccine effectiveness estimates without frailty, with frailty as continuous and categorical variable showed values of 55.2% (95% CI: 30.5, 74.2), 60.4% (95% CI: 29.5, 74.4), and 54.3% (95% CI: 28.8, 74.0), respectively [34]. In contrast to other study designs, frailty doesn’t seem to produce a substantial bias in TND influenza vaccine effectiveness studies.

8.4 Seasonal influenza vaccine effectiveness results for older adults in eight

post-pandemic influenza seasons

Information was gathered on seasonal vaccine effectiveness in older adults during eight seasons starting from 2010/2011.

Only adjusted influenza vaccine effectiveness results are included into the analysis, in cases without adjustments crude effectiveness results were included as well. An overview of the results is seen in Table 3, whereas Table 4 shows necessary information on assessment of vaccination status, sampling time and used case definition of each study.

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Table 3. Overview of the studies included in the results with corresponding selected information and adjusted SIVE.

Season Region Country/ Consortium Study Study design Influenza confirmation Hospital/ Outpatient/ Both Study population No. Cases/ vaccinated No./ % Controls/ vaccinated No./% Adjusted SIVE (CI 95%) SIVE against subtype 2010/ 2011 North America USA Treanor JJ et al. TND RT-PCR both 425 63/40/63 358/258/72 46 (-22 to 66) both influenza A subtypes Havers F et al. TND RT-PCR hospital 1141 368/204/55 773/489/63 57 (34 to 72) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR both 338 116/not specified 222/not specified 26 (−28 to 57) all influenza subtypes Kwong JC et al. TND RT-PCR hospital 2230 569/238/ 42 1661/934/ 56 42 (29 to 53) all influenza subtypes Europe IMOVE+ Kissling E et

al. TND RT-PCR or culture outpatient 469 130/not specified 339/not specified 63 (33 to 79) all influenza subtypes Spain Martínez-baz I et al. TND RT-PCR both 98 45/10/22 53/36/68 69 (0 to 91) all influenza subtypes Puig-Barbera J et al. TND RT-PCR hospital 136 43/not specified 93/not specified 59 (16 to 76) all influenza subtypes UK Pebody RG et al. TND RT-PCR outpatient 484 53/not specified 431/not specified 73 (0 to 85) influenza A(H1N1) 2011/ 2012 North America USA Ohmit SE et al. TND RT-PCR outpatient 384 53/32/60.4 331/254/76.7 43 (-18 to 72) all influenza subtypes Talbot HK et al. TND RT-PCR hospital 137 13/not specified 124/not specified 77 (24 to 98) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR outpatient 407 99/31/31 308/164/53 58 (30 to 75) all influenza subtypes Europe IMOVE+ Kissling E et

al. TND RT-PCR or culture outpatient 516 244/not specified 272/not specified 15 (-33 to 46) influenza A(H3N2) Spain Puig-Barberà J et al. TND RT-PCR hospital 1511 457/294/64 1054/705/67 21 (25 to 40) influenza A(H3N2) UK Pebody RG et al. TND RT-PCR outpatient 451 28/not specified 423/not specified 48 (-50 to 82) influenza A(H3N2) 2012/ 2013 North America USA Jackson L et al. TND RT-PCR outpatient 290 125/not specified 165/not specified 27 (-31 to 59) Interim estimates all influenza subtypes McLean HQ TND RT-PCR outpatient 866 434/135/31 432/not

specified 26 (−10 to 50) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR outpatient 437 171/54/32 266/126/47 47 (17 to 66) all influenza subtypes Europe IMOVE+ Kissling E TND RT-PCR

or culture outpatient 362 131/38/29 231/100/43 Crude aVE: 44 (9 to 66) influenza B Spain Martínez-Baz et al. TND RT-PCR both 94 27/11/40 67/47/70 75 (22 to 92) all influenza subtypes UK Pebody RG et al. TND RT-PCR outpatient 228 32/not specified 196/not specified 65 (18 to 85) influenza B

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21 2013/ 2014 North America USA Flannery B et al. TND RT-PCR outpatient 242 57/35/61 185/146 52 (2-77) Interim estimates all influenza subtypes Gaglani M et al. TND RT-PCR outpatient 602 81/54/67 521/434/83 59 (25– 77) influenza A(H1N1) Canada McNeil S et al. TND RT-PCR or culture hospital 994 248/not specified 746/not specified 58 (35 to 73) Interim estimate all influenza subtypes Skowronski DM et al. TND RT-PCR outpatient 149 41/not specified 108/not specified 60 (15– 82) all influenza subtypes IMOVE+ Valenciano M et al. TND RT-PCR outpatient 226 42/15/36 184/96/52 Crude aVE: 49 (−2 to 75) influenza A(H1N1) Spain Dominguez A et al. TND RT-PCR, culture, immune- fluorescence hospital 1471 433/208/48 1038/602/58 37 (19 to 51) all influenza subtypes UK - - - - 2014 /2015 North America USA Flannery B et al. TND RT-PCR outpatient 660 272/192/71 388/293/76 23 (-14 to 47) interim estimate all influenza subtypes Zimmerman RK et al. TND RT-PCR outpatient 1206 348/274/79 858/727/85 32 (3 to 52) all influenza subtypes Canada McNeil SA et al. TND RT-PCR or culture hospital 854 517/365/71 337/234/69 −25 (-65 to 5) Interim estimate all influenza subtypes Gilca R et al. TND RT-PCR hospital 314 186/116/62 128/75/59 -14 (-82 to 29) Mid-season estimate influenza A(H3N2) Skowronski DM et al. TND RT-PCR outpatient 252 113/not specified 139/not specified 20 (−47 to 57) all influenza subtypes Europe IMOVE+ Valenciano

M et al. TND RT-PCR outpatient 741 270/114/42 471/210/45 16 (-20 to 41) influenza A(H3N2) Castilla J et al. TND RT-PCR both 389 177/109/62 212/138/65 14 (−33 to 45) all influenza subtypes Dominguez A et al. TND RT-PCR, culture, immuno-fluorescence hospital 1083 295/151/51 788/451/57 34 (10 to 52) all influenza subtypes UK Pebody RG et al. TND RT-PCR outpatient 334 84/not specified 250/not specified 33 (−45 to 69) influenza A(H3N2) 2015/ 2016 North America USA Jackson L et al. TND RT-PCR outpatient 838 109/not specified not specified 42 (8 to 65) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR outpatient 183 72/42/58 111/77/60 43 (-26 to 74) influenza A(H1N1) Europe IMOVE+ Rondy M et

al. TND RT-PCR hospital 1331 355/138/39 976/543/56 42 (22 to 57) influenza A(H1N1) Spain Puig-Barbera J et al. TND RT-PCR hospital 1049 187/105/56 862/539/63 3 (-39 to 33) all influenza subtypes UK Pebody RG et al. TND RT-PCR outpatient 427 63/not specified 364/not specified 29 (34 to 62) all influenza subtypes 2016/ 2017 North America USA Flannery B et al. TND RT-PCR outpatient 459 128/100/78 331/271/82 46 (4 to 70) Interim all influenza subtypes

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22 estimate Ferdinands J TND RT-PCR hospital 978 197/139/71 781/621/80 37 (8 to 57) all influenza subtypes Ferdinands J TND RT-PCR outpatient 1017 326/248/76 691/554/80 25 (-5 to 46) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR outpatient 122 53/28/53 69/48/70 No age related data yet -

Europe IMOVE+ Kissling E et al. TND RT-PCR outpatient 546 278/140/50 268/144/54 23 (15 to 49) Early estimate influenza A(H3N2) Rondy M et al. TND RT-PCR hospital 556 240/95/40 316/162/51 3 (-52 to 37) Early estimate influenza A(H3N2) Rondy M et al. TND RT-PCR hospital 2614 1073/556/52 1541/894/58 17 (1 to 31) influenza A(H3N2) Spain Mira-Iglesias A et al. TND RT-PCR hospital 1094 196/111/57 898/537/60 19 (-15 to 43) all influenza subtypes UK Pebody RG et al. TND RT-PCR outpatient 398 85/63/74 313/204/65 -6 (-95 to 42) all influenza subtypes 2017/ 2018 North America USA Flannery B et al. TND RT-PCR outpatient 584 216/157/73 368/285/78 18 (-25 to 47) Interim estimate all influenza subtypes Rolfes AM et al. TND RT-PCR outpatient 1158 415/317/76 743/594/80 17 (-14 to 39) all influenza subtypes Canada Skowronski DM et al. TND RT-PCR outpatient 215 98/59/60 117/89/76 No age related data yet -

Europe IMOVE+ Kissling E et al. TND RT-PCR outpatient 496 234/110/47 262/128/49 44 (8 to 66) Interim estimate all influenza subtypes Rondy M et al. TND RT-PCR hospital 931 385/200/52 546/332/61 35 (13 to 51) Interim estimate all influenza subtypes Spain Castilla J et al. TND RT-PCR both 687 299/190/64 388/277/71 30 (2 to 50) Interim estimate all influenza subtypes UK Public Health England TND RT-PCR outpatient not specified not specified not specified 10 (-55 to 48) all influenza subtypes 8.4.1 2010/2011 season

The vaccine effectiveness in the United States was volatile. Two studies provided information about the VE in this season: the first one stated a VE of 46% [36]. The results of this study assumed a protection in the elderly, but have to be put into relation to the decreased number of involved subjects. The second study’s VE was 57% [37].The first study shows a lower vaccine protection compared to the second one. In order to compare the results it is important to keep in mind that the first study included outpatient and hospital cases, whereas the second one exclusively included hospitalized

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patients. In Canada mostly two studies also observed VE in this season. Firstly, the data from the inner country influenza surveillance showed a VE of 26% [38]. The second Canadian study focused entirely on older adults and yielded an influenza vaccine effectiveness of 42% [39]. This is important for test-negative studies to know whether influenza is still detectable. For the European region the IMOVE+ network study, which in this season consisted of data from the countries France, Hungary, Ireland, Italy, Poland, Portugal, Romania and Spain, showed a VE of 63 % as a summary across all eight countries [40]. The results of the study showed a protective value for elderly throughout Europe during this season.

In Spain separately, two studies were done in this season: one in Navarre had a VE of 69% [41]. The study included all age groups, but only the value for persons over the age of 50 years are included in this thesis.

The second one in Valencia resulted in an aVE of 59% [42]. The aim of the study was to show aVE in Valencia, Spain. In the United Kingdom study results showed a vaccine effectiveness of 73% [43]. Data was taken from all UK countries (Wales, England, Scotland, Northern Ireland).

During this season, the lowest effectiveness across the observed countries was the Canadian hospital/outpatient study. In North America, the pure hospital studies showed a higher vaccine effectiveness than the mixed ones. The hospital study in the United States as well as in Canada had a larger study population, which assumes the results are more statistically significant. When comparing North America to Europe every included European study yielded a higher effectiveness than the North American counterparts. Among European countries, the United Kingdom protruded against the IMOVE+ network study and Spain. Vaccination in older adults was highly effective in Europe and therefore older adults received a good protection against an influenza virus infection.

8.4.2 2011/2012 season

The vaccine effectiveness in this season in the USA was 43% as stated in one study [44]. The study included all age groups, but here only the elderly persons are included. A second American study showed the result of 77% in people over 50 years of age [45]. The results showed a relatively good protection for patients over 50 years of age during the 2011/2012 season.

With 58% Canada had a higher VE than the USA [46]. The results are comparable to the US results during this season.

The effectiveness in Europe according to the IMOVE+ study, which averaged data of the eight countries France, Hungary, Ireland, Italy, Poland, Portugal, Romania and Spain, was 15% [47]. The aVE was only estimated for the most common circulating virus subtype in Europe, which was

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influenza A (H3N2). The results showed a lower adjusted vaccine effectiveness across the observed European countries. This is in contrast to the relatively good results in North America during this season.

Spain had separately done one estimation study. First one was being conducted in the region of Valencia and yielded an adjusted vaccine effectiveness of 21% [48]. The results of this study are comparable to this year’s IMOVE+ study and exhibit that there was a less protective effect of the 2011/2012 vaccine in elderly in Spain.

The United Kingdom showed an aVE of 48% during the 2011/2012 season in people over 65 years of age [49]. Data was derived from all countries of the UK. Only influenza A (H3N2) and influenza B (both lineages) were included into the study.

In the USA two studies were conducted, in which the hospital one revealed a higher vaccine effectiveness compared to the outpatient study. The Canadian estimate showed a good protection and is situated in between the values of the two US studies. Europe generally had a lower influenza vaccine effectiveness compared to North America. From the European studies, the UK yielded the highest VE like in the previous season. The vaccine effectiveness showed no relation to the population criteria of the study (hospital/outpatient).

8.4.3 2012/2013 season

Interim results for the USA displayed an adjusted vaccine effectiveness of 27% [50]. Interim results are reports about the VE before the end of influenza season (in this case until the mid of January). Because only the first months of the influenza season are involved, it can’t be attributed to the whole influenza season. The interim results for the USA exhibited a lower protective value of the vaccine in patients over 65 years of age. Whole season vaccine effectiveness in the USA was described by one study and was estimated as 26% [51]. The results are similar to the interim estimations and express that the protection against influenza for elderly was lower during this season. Canada’s vaccine effectiveness was 47% as reported in one published study [52]. Practitioners from the five most-populous provinces (British Columbia (BC), Alberta, Manitoba, Ontario and Quebec) were recruiting subjects for the study. The results show a better protection in elderly and stands in contrast to other results in North America. In Europe, the IMOVE+ study had too few cases in persons over the age of 65 to make an adjustment of crude VE. The crude vaccine effectiveness determined in the European study for the three influenza subtypes A(H1N1), A(H3N2) and B was 44%, 59%, 37% respectively [53]. The test-negative case-control study had seven study sites located in France, Germany, Ireland, Poland, Portugal, Romania and Spain. Among the elderly the crude VE expressed a lower protection against Influenza B and Influenza A H3N2, the protection against Influenza A H1N1 was better. The

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results show similarities to this season’s North America results. The Spanish study during this season evaluated the aVE as 71% [54]. The United Kingdom had one study, which showed a vaccine effectiveness of -14% against the predominating H3N2 subtype [49]. The results indicate a lower protection against influenza for elderly during this season and are comparable to the North American results.

The interim estimate in the United States was nearly identical to the end-of-season value (-1%) of influenza vaccine effectiveness. Compared to Canada, both US studies exhibited a lower vaccine effectiveness. Spain and the UK showed a good protective value of influenza vaccine in their studies. The IMOVE+ study had a lower result than the other European countries, which may have also resulted from the fact that there were too few cases for adjustment and only the crude VE being available. The influenza vaccine effectiveness was generally better in Europe than in the North American countries.

8.4.4 2013/2014 season

During the season the interim estimate in the USA showed a VE of 52% against influenza A (H1N1) [55]. In this case the results show a relatively good protection for elderly against influenza A (H1N1) this season.

The full-season results for the USA were 59% and therefore similar to the interim results [56]. The results are in accordance with the interim results published earlier and suggest a relatively good protection against a H1N1 infection.

Canada showed a vaccine effectiveness of 58% in their interim estimation [57].

The full-season results estimated the VE against predominating influenza A(H1N1) in Canada as 60% [58]. The study evaluated the vaccine effectiveness across Canada in a H1N1 predominated season. The results were similar to this season’s interim results, which were previously published. In Europe the IMOVE+ Study, like in the previous season, had too few cases to make an adjustment. The crude vaccine effectiveness of the test-negative case-control study was 49% [59]. Six study sites contributed to this season’s European study (Germany, Hungary, Ireland, Portugal, Romania and Spain). A Spanish study for this season estimated an adjusted vaccine effectiveness of 37% [60]. The multicenter case-control study was conducted in 20 major hospitals in 7 out of 18 regions in Spain (Andalusia, the Basque Country, Catalonia, Castile and Leon, Madrid, Navarra and Valencian Community). Patients over the age of 65 were included if they were hospitalized for at least 24 hours with a laboratory-confirmed influenza virus. For each case up to three controls, with hospitalization with other causes

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than influenza or ARI were selected. For the United Kingdom no results were available during this season.

The interim estimate in the Unites States was, like in the 2012/2013 season, close to the end-of-season estimate (7% difference). The same relation is observed in Canada, where the difference between interim estimate und full-season values is only 2%. All North American results are between 50 to 60% of vaccine effectiveness, which indicates a good protective value. In Europe the vaccine effectiveness was lower than in the USA and Canada, with the IMOVE+ study having a higher VE than the Spanish one. For the United Kingdom, no study with values for older adults was available during this season.

8.4.5 2014/2015 season

The early estimate predicted a VE of 23 % in the USA [61]. The estimate was performed to evaluate the vaccine effectiveness for preventing influenza cases in an outpatient setting at an early point of influenza season (January 2015). The results suggest a lower protective effect of this year’s vaccination. The results of the whole influenza season in the USA were displayed by one study as 32 % [62]. The results show a diminished protection against influenza during this season with antigenic mismatch. The result is higher compared with the early season results, suggesting that the protection was better in the second half of the season. In Canada the mid-season estimate was 14% [63]. The test-negative case control study included only elderly and aimed to determine vaccine effectiveness against the predominating influenza A (H3N2) type. Patients were included if they were in one of the sentinel hospitals of Quebec for more than 24 hours and initially presenting with cough, sore throat, or fever/feverishness of unknown etiology. The Canadian mid-season report in Quebec shows a lower protection in the elderly. The interim estimate in Canada yielded -25 % as a result [64]. The results of the interim estimate show a low protection and match the mid-season result. The Canadian whole season result showed a value of 20% [65]. The whole season results show a lower protection against influenza in Canada. But compared to the mid-season and interim estimate the protective value increased slightly. The IMOVE+ study showed a vaccine effectiveness of 16% across selected European countries [66]. Eight study sites (Germany, Hungary, Ireland, Italy, Poland, Portugal, Romania and Spain) contributed data to this multicenter estimate. The results are in accordance to other northern hemisphere of this season and show a lower protection in the elderly during this season. Spain evaluated the effectiveness in two studies. 14% was the result of vaccine effectiveness in the Navarre study [67]. As the name indicates the study was performed in the region of Navarre, Spain to evaluate the vaccine effectiveness in this region. It indicates a lower protection against influenza during this season. Results for this season also came from the multicenter study,

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which was already introduced in the season before. It showed a vaccine effectiveness of 34% [60]. The results are in contrast to the results from other countries in the Northern hemisphere, indicating a moderate influenza vaccine effectiveness. According to values of one study the UK had a VE of 44% [68]. All member countries of the United Kingdom contributed data to this study. In contrast to most European and North American results these results show a better protection against the influenza virus in the elderly.

This season showed a low influenza vaccine effectiveness across nearly all observed countries. In the USA, the interim estimate was lower than the end-of-season one. The Canadian interim and mid-season estimates even had negative influenza vaccine effectiveness values. The whole mid-season vaccine of effectiveness in the United States was higher than the counterpart in Canada. Europe showed low to moderate effectiveness rates. Especially the IMOVE+ study and the Spanish mixed hospital/outpatient study had low results, compared to more moderate results of the second Spanish study and UK results.

8.4.6 2015/2016 season

The vaccine effectiveness in the USA was 42% according to one published study [69]. The study demonstrates a moderate effectiveness of the vaccine against the influenza virus during this season. The same vaccine effectiveness percentage was shown by one test-negative case-control study in Canada [70]. It shows a average protection for elderly persons during this season in Canada. The IMOVE+ study found a similar effectiveness across Europe, with a value of 42% [71]. For this season, there were more study sites included than in the IMOVE+ studies during the previous seasons. 27 hospitals in 11 different countries (Croatia, Finland, France, Hungary, Italy, Lithuania, the Netherlands, Poland, Portugal, Romania and Spain) contributed data to the European study. A Spanish study conducted in Valencia showed a VE of only 3% [72]. The study included data from four hospitals around the region of Valencia The results are lower than in studies from other countries during this season and suggest a low protective vaccine value in Spain. In the United Kingdom one study evaluated the vaccine effectiveness as 29% [73]. The results show a relevant protection as more than half of influenza infections were prevented by the vaccination.

In North America, only outpatient studies included data of older adults and yielded close to identical results, indicating a moderate influenza vaccine effectiveness during this season. Among Europe, the study conducted by the IMOVE+ network showed higher results than Spain and in the United Kingdom. Spain showed the lowest VE results during this season in their conducted hospital study.

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The results of North America were higher than corresponding European results. The USA, Canada and the IMOVE+ study showed moderate, the United Kingdom low to moderate and Spain low results.

8.4.7 2016/2017 season

The vaccine effectiveness in the USA was 46% according to the interim estimate [74]. Canada had no data on vaccine effectiveness in the elderly age group available for this season. The European IMOVE+ study showed a VE of 23% (outpatient) and 3% (hospital) for selected countries in Europe in their early estimate [75]. Patients were enrolled from the primary care and hospital setting into the test-negative case-control study. Compared to other age groups, the sample size of the elderly was quite low. This may have led to imprecision in the estimates. The estimates by the IMOVE+ study suggest a lower protection across Europe during this season. A whole season estimate, conducted by the IMOVE+ network as well, revealed a vaccine effectiveness of 17% [76]. The study concentrated exclusively on older adults as study population. Data was gathered from 27 hospitals in 10 European countries (Croatia, Finland, France, Hungary, Italy, Lithuania, the Netherlands, Portugal, Romania and Spain). A Spanish study showed an inner country influenza vaccine effectiveness of 19% in persons over the age of 60 years [77]. The study was carried out in four hospitals in the Valencia region. The United Kingdom had a vaccine effectiveness against laboratory confirmed influenza of -6 % by one major study [78]. The test-negative case-control study included all countries of the UK. The results suggest that vaccination during season in the United Kingdom was not effective.

The interim estimate of the USA was higher than the full-season results, independent from wether the full-season study included outpatient or hospitalized patients. The whole season hospital study yielded a higher VE than the outpatient counterpart. In general it can be stated that the aVE was moderate in the United States during this season. As no age related data was available for Canada during this season, no comparison can be made. The early estimate of the IMOVE+ study, was split into a hospital one and outpatient one. The hospital study evaluated a higher vaccine effectiveness than the outpatient one. All IMOVE+ studies concluded an ineffective influenza vaccination in older adults. In Spain and the United Kingdom vaccine effectiveness appeared to be in accordance with the results from IMOVE+ and displayed a low protective influenza vaccine value. The US estimates were higher compared to the included European results.

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8.4.8 2017/2018 season

The United States conducted two studies on this season’s influenza vaccine effectiveness, including data on older adults. The first one was an interim estimate yielding an aVE of 18% [79]. The second US study involved the entirety of the influenza season and revealed an aVE of 17% [80]. Canada had no age related data for older adults available during this season in the research period.

The IMOVE+ network provided two interim studies this season: one with outpatient and one with hospitalized patients. The outpatient study included data from Croatia, France, Germany, Ireland, Italy, the Netherlands, Portugal, Spain and Sweden and had a resulting VE of 44% [81]. The hospital study included data from France, Italy, the Netherlands, Portugal and Spain and published a vaccine effectiveness result of 35% [81]. During this season one study evaluated the inner Spanish VE in the region of Navarre. The interim estimate revealed an aVE of 30% [82]. In the United Kingdom one study yielded an aVE result of 10% in older adults [83].

During the season, the interim estimate of the USA was close to the VE of the entire season (difference of 1%). It displayed that the United States had a low vaccine effectiveness in the 2017/2018 season. Like in the previous season, Canada had no age-related data available. Compared with the USA, the European results showed a more moderate VE (IMOVE+, Spain). Only the United Kingdom had a lower result and therefore the most ineffective influenza vaccination during this season. Like in the last season the IMOVE+ study was split into a hospital and outpatient study. The outpatient study showed a higher vaccine effectiveness than the hospital one.

Table 4. Sampling time, case definitions and assessment of vaccination status of included studies

Season Region Country/ Consortium

Study Sampling time ILI/ARI Vaccination status assessment

2010/ 2011

North America

USA Treanor JJ et al. Within 7 days of symptom onset

ARI Self-report, medical records, vaccine registries

Havers F et al. Not defined ILI Self-report, medical records

Canada Skowronski DM et al.

Within 7 days of symptom onset

ILI Self-report

Kwong JC et al. Not defined Vaccine registries

Europe IMOVE+ Kissling E et al. Within 8 days of symptom onset ILI and ARI Self-report Spain Martínez-baz I et al. Within 5 days of symptom onset

ILI Vaccine registries

Puig-Barbera J et al.

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UK Pebody RG et al. Not defined ILI Medical records

2011/ 2012

North America

USA Ohmit SE et al. Within 7 days of symptom onset

ARI Medical records

Talbot HK et al. Within 10 days of symptom onset

ARI Medical records

Canada Skowronski DM et al.

ILI Self-report

Europe IMOVE+ Kissling E et al. Within 8 days of symptom onset ILI Self-report Spain Puig-Barberà J et al. Within 7 days of symptom onset

ILI Self-report and vaccine registries

2012/ 2013

North America

USA Jackson L et al. Within 7 days of symptom onset

McLean HQ Within 7 days of symptom onset

ARI Medical records, vaccine registries Canada Skowronski DM et al. Within 7 days of symptom onset ILI Self-report

Europe IMOVE+ Kissling E Within 7 days of symptom onset ILI Self-report Spain Martínez-Baz et al. Within 5 days of symptom onset

2013/ 2014

North America

USA Flannery B et al. Within 7 days of symptom onset

ARI Medical records, vaccine registries

Gaglani M et al. Within 7 days of symptom onset

Canada McNeil S et al. Not defined ILI Self-report, medical records, vaccine registries Skowronski DM et al. Within 7 days of symptom onset ILI Self-report IMOVE+ Valenciano M et al. Within 7 days of symptom onset ILI Self-report Spain Dominguez A et al.

Not defined Not defined Self-report UK - - - - 2014 /2015 North America

ARI Medical record and vaccine registries

Zimmerman RK et al.

ARI Self-report, medical records and vaccine registries

Canada McNeil SA et al. Self-report and vaccine registries

Gilca R et al. Within 7 days of symptom onset Not defined Medical records Skowronski DM et al.

Not defined Not defined

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Europe IMOVE+ Valenciano M et al.

ILI Medical records or self-report

Spain Castilla J et al. Within 5 days of symptom onset

ILI Vaccine register

Dominguez A et al.

Not defined Not defined

Self-report

UK Pebody RG et al. Within 7 days of symptom onset

ILI Medical records

2015/ 2016

North America

USA Jackson L et al. Within 7 days of symptom onset

ARI Medical records and vaccine registries Canada Skowronski DM et al. Within 7 days of symptom onset ILI Self-report

Europe IMOVE+ Rondy M et al. Within 7 days of symptom onset

ARI Self-report or vaccine registries

Spain Puig-Barbera J et al.

ILI Self-report and vaccine registries

UK Pebody RG et al. Not defined ILI Self-report

2016/ 2017

North America

ARI Medical records and vaccine registries

Ferdinands J (outpatient)

ARI Self-report, medical records and vaccine registries Ferdinands J (hospital) Within 10 days of symptom onset ARI Self-report Canada Skowronski DM et al. Within 7 days of symptom onset ILI Self-report

Europe IMOVE+ Kissling E et al. Within 7 days of symptom onset

ILI and ARI

Self-report

Rondy M et al. Within 7 days of symptom onset

ILI and ARI

Self-report

Rondy M et al. Within 7 days of symptom onset ARI Self-report Spain Mira-Iglesias A et al. Within 7 days of symptom onset

UK Pebody RG et al. Within 7 days of symptom onset

ILI Medical records

2017/ 2018

North America

ARI Medical records and vaccine registries

Rolfes AM et al. Within 7 days of symptom onset

ARI Medical records and vaccine registries Canada Skowronski DM et al. Within 7 days of symptom onset ILI Self-report

Europe IMOVE+ Kissling E et al. Within 7 days of symptom onset

ILI Medical records

Rondy M et al. Within 7 days of symptom onset

ARI Self-report, medical records and vaccine registries

Spain Castilla J et al. Within 5 days of symptom onset

ILI Not defined

UK Public Health

England

Not specified Not specified

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9. Discussion

Over all eight seasons of the observations, the predominant circulation of the influenza strains changed nearly every season. The influenza A(H3N2), the subtype connected to the highest influenza mortality, was more prevalent in the USA and Canada, whereas the influenza A(H1N1) subtype appeared more often in European countries. The least common subtype was influenza B, which in several seasons co-fluctuated with another subtype. The European 2017/2018 season was the first one with a solely predomination of influenza B. Influenza surveillance is important to identify mismatches with influenza vaccine and define the recommendations for influenza vaccine production for the following season.

Vaccine and predominant influenza strain mismatch in the included eight season may have occurred because of an antigenic drift. These minor changes to the antigenic properties of a strain are believed to be caused by point mutations in the segments of RNA gene that are responsible for neuraminidase and hemagglutinin. The mismatch can also be caused by mutations in the production process of vaccine. Several studies describe that the egg-adaptation of the prototype virus suggested by the WHO is responsible for the mismatch with circulating strain [52] [84]. This egg-adaptation is needed in the production of vaccines to produce them in a large scale. The matches and mismatches throughout the seasons differ geographically. An example for this is the 2017/2018 season where a mismatch of the predominating influenza B(Yamagata) with the vaccine strain (Victoria) occurred in Europe, but in USA the predominating influenza A(H3N2) matched the strain contained in the vaccine. Throughout the eight season there were more mismatches in Europe compared to North America.

The TND appears to have a comparable validity than the bigger populated randomized controlled trials in older adults [30]. Beside the validity, advantages of the TND are the simplicity of implementation and the reduced influence of bias on the evaluated influenza vaccine effectiveness [85]. Especially in older adults, a bias as frailty can be effectively reduced by this study design [34]. Taking in comparison the advantages and disadvantages of the TND, it appears that all upcoming VE evaluation studies should use this design.

The vaccine effectiveness results differ from season to season and between different countries. Generally, the effectiveness of the influenza vaccine seems to be moderate to good. But as the results also show a full season with low effectiveness results and certain other seasons with low country specific results, it has to be established how these variations occur. One explanation of diminished seasonal vaccine effectiveness throughout the results is a mismatch between the predominating virus and the vaccine composition recommendation by the WHO. As an example, the 2014/2015 season showed a genetic/antigenic variation of the predominating virus in contrast to the vaccine composition among all the observed countries. In all countries during this season (except the United Kingdom), the

Lithuanian University of Health Sciences Faculty of Medicine

Table of contents

1. Summary

2. Acknowledgements

3. Conflict of Interest

4. Abbreviations

5. Introduction

6. Aim and Objectives

7. Research methodology and methods

8. Results

8.1

Influenza Virus Circulation in Northern Hemisphere from 2010 to 2018

8.2 Influenza vaccine composition and it’s match/mismatch with circulating strains

8.3 Methods used in influenza vaccine effectiveness evaluations

8.4 Seasonal influenza vaccine effectiveness results for older adults in eight

post-pandemic influenza seasons

9. Discussion