Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis.

One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV-positive and PAN-negative control groups. A total of 63 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (ΔVE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group.

Inter-Seasonal Influenza is Characterized by Extended Virus Transmission and Persistence.

The factors that determine the characteristic seasonality of influenza remain enigmatic. Current models predict that occurrences of influenza outside the normal surveillance season within a temperate region largely reflect the importation of viruses from the alternate hemisphere or from equatorial regions in Asia. To help reveal the drivers of seasonality we investigated the origins and evolution of influenza viruses sampled during inter-seasonal periods in Australia. To this end we conducted an expansive phylogenetic analysis of 9912, 3804, and 3941 hemagglutinnin (HA) sequences from influenza A/H1N1pdm, A/H3N2, and B, respectively, collected globally during the period 2009-2014. Of the 1475 viruses sampled from Australia, 396 (26.8% of Australian, or 2.2% of global set) were sampled outside the monitored temperate influenza surveillance season (1 May - 31 October). Notably, rather than simply reflecting short-lived importations of virus from global localities with higher influenza prevalence, we documented a variety of more complex inter-seasonal transmission patterns including "stragglers" from the preceding season and "heralds" of the forthcoming season, and which included viruses sampled from clearly temperate regions within Australia. We also provide evidence for the persistence of influenza B virus between epidemic seasons, in which transmission of a viral lineage begins in one season and continues throughout the inter-seasonal period into the following season. Strikingly, a disproportionately high number of inter-seasonal influenza transmission events occurred in tropical and subtropical regions of Australia, providing further evidence that climate plays an important role in shaping patterns of influenza seasonality.

Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza.

A debate about the market-leading influenza antiviral medication, oseltamivir, which initially focused on treatment for generally mild illness, has been expanded to question the wisdom of stockpiling for use in future influenza pandemics. Although randomized controlled trial evidence confirms that oseltamivir will reduce symptom duration by 17-25 hours among otherwise healthy adolescents and adults with community-managed disease, no randomized controlled trials have examined the effectiveness of oseltamivir against more serious outcomes. Observational studies, although criticized on methodologic grounds, suggest that oseltamivir given early can reduce the risk for death by half among persons hospitalized with confirmed infection caused by influenza A(H1N1)pdm09 and influenza A(H5N1) viruses. However, available randomized controlled trial data may not be able to capture the effect of oseltamivir use among hospitalized patients with severe disease. We assert that data on outpatients with relatively mild disease should not form the basis for policies on the management of more severe disease.

Influenza vaccine effectiveness in general practice and in hospital patients in Victoria, 2011-2013.

OBJECTIVE: To compare influenza vaccine effectiveness in the general practice and hospital settings. DESIGN: Analysis of annual case test-negative studies. SETTING: Victorian sentinel hospitals and general practices, 2011-2013. PARTICIPANTS: Patients presenting to general practitioners, or those admitted to hospital with an influenza-like illness who were tested for influenza using a polymerase chain reaction assay. Cases were patients with a positive test result for influenza; non-cases (controls) had a negative test result. MAIN OUTCOME MEASURES: Vaccine effectiveness against laboratory-confirmed influenza. RESULTS: Hospitalised patients were on average older and reported a higher proportion of comorbidities than general practice patients. The pooled estimate of influenza vaccine effectiveness against laboratory-confirmed infection for the 3 years was 50% (95% CI, 26%-66%) for general practice patients and 39% (95% CI, 28%-47%) for patients admitted to hospital. CONCLUSIONS: Influenza vaccines appeared to be similarly modestly effective in the general practice and hospital settings. Influenza vaccination appears to prevent hospital admission by preventing symptomatic infection rather than by attenuating the severity of illness.

Flutracking weekly online community survey of influenza-like illness annual report, 2015.

Flutracking is a national online community influenza-like illness (ILI) surveillance system that monitors weekly ILI activity and impact in the Australian community. This article reports on the 2015 findings from Flutracking. From 2014 to 2015 there was a 38.5% increase in participants to 27,824 completing at least 1 survey with a peak weekly response of 25,071 participants. The 2015 Flutracking national ILI weekly fever and cough percentages peaked in late August at 5.0% in the unvaccinated group, in the same week as the national counts of laboratory confirmed influenza peaked. A similar percentage of Flutracking participants took two or more days off from work or normal duties in 2015 (peak level 2.3%) compared with 2014 (peak level 2.5%) and the peak weekly percentage of participants seeking health advice was 1.6% in both 2014 and 2015. Flutracking fever and cough peaked in the same week as Influenza Complications Alert Network surveillance system influenza hospital admissions. The percentage of Flutracking participants aged 5 to 19 years with cough and fever in 2015 was the highest since 2011. The 2015 season was marked by a transition to predominantly influenza B strain circulation, which particularly affected younger age groups. However, for those aged 20 years and over, the 2015 national Flutracking influenza season was similar to 2014 in community ILI levels and impact.

Hospitalization Fatality Risk of Influenza A(H1N1)pdm09: A Systematic Review and Meta-Analysis.

During the 2009 influenza pandemic, uncertainty surrounding the severity of human infections with the influenza A(H1N1)pdm09 virus hindered the calibration of the early public health response. The case fatality risk was widely used to assess severity, but another underexplored and potentially more immediate measure is the hospitalization fatality risk (HFR), defined as the probability of death among H1N1pdm09 cases who required hospitalization for medical reasons. In this review, we searched for relevant studies published in MEDLINE (PubMed) and EMBASE between April 1, 2009, and January 9, 2014. Crude estimates of the HFR ranged from 0% to 52%, with higher estimates from tertiary-care referral hospitals in countries with a lower gross domestic product, but in wealthy countries the estimate was 1%-3% in all settings. Point estimates increased substantially with age and with lower gross domestic product. Early in the next pandemic, estimation of a standardized HFR may provide a picture of the severity of infection, particularly if it is presented in comparison with a similarly standardized HFR for seasonal influenza in the same setting.

Influenza vaccine effectiveness during the 2012 influenza season in Victoria, Australia: influences of waning immunity and vaccine match.

Vaccine effectiveness may wane with increasing time since vaccination. This analysis used the Victorian sentinel general practitioner (GP) network to estimate vaccine effectiveness for trivalent inactivated vaccines in the 2012 season. A test-negative design was used where patients presenting to GPs with influenza-like illness who tested positive for influenza were cases and noncases were those who tested negative. Vaccination status was recorded by GPs. Vaccine effectiveness was calculated as (1-odds ratio) × 100%. Estimates were compared early versus late in the season and by time since vaccination. Virus isolates were assessed antigenically by hemagglutination inhibition assay in a selection of positive samples and viruses from healthy adults who experienced a vaccine breakthrough were analyzed genetically. The adjusted vaccine effectiveness estimate for any type of influenza was 45% (95% CI: 8,66) and for influenza A(H3) was 35% (95% CI: -11,62). A non-significant effect of waning effectiveness by time since vaccination was observed for A(H3). For those vaccinated <93 days of presentation vaccine effectiveness was 37% (95% CI: -29,69), while for those vaccinated ≥93 days before presentation it was 18% (95% CI: -83,63). Comparison of early versus late in the season estimates was very sensitive to the cut off week chosen for analysis. Antigenic data suggested that low vaccine effectiveness was not associated with poor vaccine match among the A(H3) viruses. However, genetic analysis suggested nucleotide substitutions in antigenic sites. In 2012, the trivalent influenza vaccine provided moderate protection against influenza and showed limited evidence for waning effectiveness. Antigenic and genetic data can provide additional insight into understanding these estimates.

Case fatality risk of influenza A (H1N1pdm09): a systematic review.

BACKGROUND: During the 2009 influenza pandemic, uncertainty surrounding the seriousness of human infections with the H1N1pdm09 virus hindered appropriate public health response. One measure of seriousness is the case fatality risk, defined as the probability of mortality among people classified as cases. METHODS: We conducted a systematic review to summarize published estimates of the case fatality risk of the pandemic influenza H1N1pdm09 virus. Only studies that reported population-based estimates were included. RESULTS: We included 77 estimates of the case fatality risk from 50 published studies, about one-third of which were published within the first 9 months of the pandemic. We identified very substantial heterogeneity in published estimates, ranging from less than 1 to more than 10,000 deaths per 100,000 cases or infections. The choice of case definition in the denominator accounted for substantial heterogeneity, with the higher estimates based on laboratory-confirmed cases (point estimates = 0-13,500 per 100,000 cases) compared with symptomatic cases (point estimates = 0-1,200 per 100,000 cases) or infections (point estimates = 1-10 per 100,000 infections). Risk based on symptomatic cases increased substantially with age. CONCLUSIONS: Our review highlights the difficulty in estimating the seriousness of infection with a novel influenza virus using the case fatality risk. In addition, substantial variability in age-specific estimates complicates the interpretation of the overall case fatality risk and comparisons among populations. A consensus is needed on how to define and measure the seriousness of infection before the next pandemic.

Sevenfold rise in likelihood of pertussis test requests in a stable set of Australian general practice encounters, 2000-2011.

OBJECTIVE: To better understand the role that diagnostic test-ordering behaviour of general practitioners has on current pertussis epidemiology in Australia. DESIGN AND SETTING: Analysis of Australian general practice encounter data (from the Bettering the Evaluation and Care of Health [BEACH] program) on 13 "pertussis-related problem" (PRP) codes that were most likely to result in a pertussis laboratory test request and Australian pertussis notifications data (from the National Notifiable Diseases Surveillance System [NNDSS]) for the period April 2000 to March 2011. MAIN OUTCOME MEASURES: The change in the proportion of PRP general practice encounters with a pertussis test request between 2000 and 2011, and the change in national pertussis notifications over the same period. RESULTS: The proportion of PRP encounters resulting in a pertussis test request increased from 0.25% between April 2000 and March 2004 to 1.71% between April 2010 and March 2011 (odds ratio, 7.0; 95% CI, 5.5-8.8). The BEACH data on pertussis testing and NNDSS data on pertussis notifications were highly correlated (r = 0.99), and the notification data mirrored the likelihood of a pertussis test request in general practice. The proportion of NNDSS pertussis notifications with a polymerase chain reaction (PCR)-confirmed diagnosis increased from 16.3% between April 2000 and March 2004 to 65.3% between April 2010 and March 2011. CONCLUSION: An increase in pertussis testing following recognition of early epidemic cases may have led to identification of previously undetected infections, resulting in a further increase in notified disease and awareness among GPs. The changing likelihood of being tested may also be due to expanding availability and use of PCR testing in Australia.

Pandemic influenza H1N1: reconciling serosurvey data with estimates of the reproduction number.

BACKGROUND: During the 2009 pandemic of influenza A (H1N1), many studies reported estimates of the reproduction number from outbreak data. Since then, seroprevalence studies have been conducted in a number of countries to assess the proportion of the population that was infected in the first wave of the pandemic. METHODS: Here, we collate the reproduction number estimates, and use mathematical models to reconcile these with serosurvey data. RESULTS: Most estimates of the reproduction number from outbreaks are in the range of 1.0-2.0, whereas mean estimates calculated from seroprevalence data range from 1.14 to 1.36. Age-specific analysis of these data suggests that the reproduction number for children was approximately 1.6, whereas the reproduction numbers for adults >25 years of age was less than 1.0. CONCLUSION: The difference between age-groups may help to explain high estimates of the reproduction number from outbreaks involving a large proportion of child cases.

Household transmission of 2009 pandemic influenza A (H1N1): a systematic review and meta-analysis.

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, household transmission studies were implemented to better understand the characteristics of the transmission of the novel virus in a confined setting. METHODS: We conducted a systematic review and meta-analysis to assess and summarize the findings of these studies. We identified 27 articles, around half of which reported studies conducted in May and June 2009. RESULTS: In 13 of the 27 studies (48%) that collected respiratory specimens from household contacts, point estimates of the risk of secondary infection ranged from 3% to 38%, with substantial heterogeneity. Meta-regression analyses revealed that a part of the heterogeneity reflected varying case ascertainment and study designs. The estimates of symptomatic secondary infection risk, based on 20 studies identifying febrile acute respiratory illness among household contacts, also showed substantial variability, with point estimates ranging from 4% to 37%. CONCLUSIONS: Transmission of the 2009 pandemic virus in households appeared to vary among countries and settings, with differences in estimates of the secondary infection risk also partly due to differences in study designs.

Evaluation of the World Health Organization global measles and rubella quality assurance program, 2001-2008.

BACKGROUND: During 2001-2008, the Victorian Infectious Diseases Reference Laboratory (VIDRL) prepared and provided a measles and rubella proficiency test panel for distribution to the World Health Organization (WHO) measles and rubella network laboratories as part of their annual laboratory accreditation assessment. METHODS: Panel test results were forwarded to VIDRL, and results from 8 consecutive years were analyzed. We assessed the type of assays used and results achieved on the basis of the positive and negative interpretation of submitted results, by year and WHO region, for measles and rubella. RESULTS: Over time, there has been a noticeable increase in laboratory and WHO regional participation. For all panels, the proportion of laboratories in all WHO regions using the WHO-validated Dade Behring assay for measles and rubella-specific IgM antibodies ranged from 35% to 100% and 59% to 100%, respectively. For all regions and years, the proportion of laboratories obtaining a pass score ranged from 87% to 100% for measles and 93% to 100% for rubella. CONCLUSIONS: During 2001-2008, a large proportion of laboratories worldwide achieved and maintained a pass score for both measles and rubella. Measles and rubella proficiency testing is regarded as a major achievement for the WHO measles and rubella laboratory program.

Effectiveness of seasonal influenza vaccine against pandemic (H1N1) 2009 virus, Australia, 2010.

To estimate effectiveness of seasonal trivalent and monovalent influenza vaccines against pandemic influenza A (H1N1) 2009 virus, we conducted a test-negative case-control study in Victoria, Australia, in 2010. Patients seen for influenza-like illness by general practitioners in a sentinel surveillance network during 2010 were tested for influenza; vaccination status was recorded. Case-patients had positive PCRs for pandemic (H1N1) 2009 virus, and controls had negative influenza test results. Of 319 eligible patients, test results for 139 (44%) were pandemic (H1N1) 2009 virus positive. Adjusted effectiveness of seasonal vaccine against pandemic (H1N1) 2009 virus was 79% (95% confidence interval 33%-93%); effectiveness of monovalent vaccine was 47% and not statistically significant. Vaccine effectiveness was higher among adults. Despite some limitations, this study indicates that the first seasonal trivalent influenza vaccine to include the pandemic (H1N1) 2009 virus strain provided significant protection against laboratory-confirmed pandemic (H1N1) 2009 infection.

No-fault compensation following adverse events attributed to vaccination: a review of international programmes.

Programmes that provide no-fault compensation for an adverse event following vaccination have been implemented in 19 countries worldwide, the first in Germany in 1961 and the most recent in Hungary in 2005. We performed a review of these programmes and determined elements that were common to all of them: administration and funding, eligibility, process and decision-making, standard of proof, elements of compensation and litigation rights. Most programmes were administered by state or national governments except in Finland and Sweden where they are coordinated by pharmaceutical manufacturers. Although funding is usually from Treasury, Taiwan (China) and the United States of America impose a tax on vaccine doses distributed. Decisions on compensation are made using established criteria or assessed on a case-by-case basis, while the standard of proof required is usually less than that required for court cases. Benefits provided by programmes include medical costs, disability pensions and benefits for noneconomic loss and death. Most countries allow claimants to seek legal damages through the courts or a compensation scheme payout but not both. We conclude that a variety of programmes, based on ethical principles, have been successful and financially viable in developed countries throughout the world. We believe there is a strong argument for widespread implementation of these programmes in other developed countries.

Estimation of type- and subtype-specific influenza vaccine effectiveness in Victoria, Australia using a test negative case control method, 2007-2008.

BACKGROUND: Antigenic variation of influenza virus necessitates annual reformulation of seasonal influenza vaccines, which contain two type A strains (H1N1 and H3N2) and one type B strain. We used a test negative case control design to estimate influenza vaccine effectiveness (VE) against influenza by type and subtype over two consecutive seasons in Victoria, Australia. METHODS: Patients presenting with influenza-like illness to general practitioners (GPs) in a sentinel surveillance network during 2007 and 2008 were tested for influenza. Cases tested positive for influenza by polymerase chain reaction and controls tested negative for influenza. Vaccination status was recorded by sentinel GPs. Vaccine effectiveness was calculated as [(1--adjusted odds ratio) × 100%]. RESULTS: There were 386 eligible study participants in 2007 of whom 50% were influenza positive and 19% were vaccinated. In 2008 there were 330 eligible study participants of whom 32% were influenza positive and 17% were vaccinated. Adjusted VE against A/H3N2 influenza in 2007 was 68% (95% CI, 32 to 85%) but VE against A/H1N1 (27%; 95% CI, -92 to 72%) and B (84%; 95% CI, -2 to 98%) were not statistically significant. In 2008, the adjusted VE estimate was positive against type B influenza (49%) but negative for A/H1N1 (-88%) and A/H3N2 (-66%); none was statistically significant. CONCLUSIONS: Type- and subtype-specific assessment of influenza VE is needed to identify variations that cannot be differentiated from a measure of VE against all influenza. Type- and subtype-specific influenza VE estimates in Victoria in 2007 and 2008 were generally consistent with strain circulation data.

Adverse events associated with 2010 CSL and other inactivated influenza vaccines.

The 2010 trivalent influenza vaccine (TIV) manufactured by CSL Biotherapies (CSL) was associated with increased febrile reactions, including febrile convulsions, among Australian children. CSL is one of the few manufacturers that use deoxycholate as the virus-splitting agent in the manufacture of TIV. Clusters of adverse events following immunisation (AEFI) have been previously linked to other deoxycholate-split TIV formulations in Europe and Canada. We hypothesise that suboptimal virus splitting or other mechanisms related to the use of deoxycholate may have played a role in adverse events linked to the 2010 CSL TIV. This hypothesis garners support from a recent United States Food and Drug Administration warning letter indicating that CSL failed to determine optimal splitting conditions for new virus strains and that assays to assess virus splitting had not been validated. While there may be other causes, the use of deoxycholate should be further explored. Comprehensive and timely investigations of AEFI, especially those involving children, are necessary to prevent their recurrence and to maintain public confidence in vaccination programs.

Modelling the effect of seasonal influenza vaccination on the risk of pandemic influenza infection.

BACKGROUND: Recent studies have suggested that vaccination with seasonal influenza vaccine resulted in an apparent higher risk of infection with pandemic influenza H1N1 2009. A simple mathematical model incorporating strain competition and a hypothesised temporary strain-transcending immunity is constructed to investigate this observation. The model assumes that seasonal vaccine has no effect on the risk of infection with pandemic influenza. RESULTS: Results of the model over a range of reproduction numbers and effective vaccination coverage confirm this apparent increased risk in the Northern, but not the Southern, hemisphere. This is due to unvaccinated individuals being more likely to be infected with seasonal influenza (if it is circulating) and developing hypothesised temporary immunity to the pandemic strain. Because vaccinated individuals are less likely to have been infected with seasonal influenza, they are less likely to have developed the hypothesised temporary immunity and are therefore more likely to be infected with pandemic influenza. If the reproduction number for pandemic influenza is increased, as it is for children, an increase in the apparent risk of seasonal vaccination is observed. The maximum apparent risk effect is found when seasonal vaccination coverage is in the range 20-40%. CONCLUSIONS: Only when pandemic influenza is recently preceded by seasonal influenza circulation is there a modelled increased risk of pandemic influenza infection associated with prior receipt of seasonal vaccine.

We should not be complacent about our population-based public health response to the first influenza pandemic of the 21st century.

BACKGROUND: More than a year after an influenza pandemic was declared in June 2009, the World Health Organization declared the pandemic to be over. Evaluations of the pandemic response are beginning to appear in the public domain. DISCUSSION: We argue that, despite the enormous effort made to control the pandemic, it is now time to acknowledge that many of the population-based public health interventions may not have been well considered. Prior to the pandemic, there was limited scientific evidence to support border control measures. In particular no border screening measures would have detected prodromal or asymptomatic infections, and asymptomatic infections with pandemic influenza were common. School closures, when they were partial or of short duration, would not have interrupted spread of the virus in school-aged children, the group with the highest rate of infection worldwide. In most countries where they were available, neuraminidase inhibitors were not distributed quickly enough to have had an effect at the population level, although they will have benefited individuals, and prophylaxis within closed communities will have been effective. A pandemic specific vaccine will have protected the people who received it, although in most countries only a small minority was vaccinated, and often a small minority of those most at risk. The pandemic vaccine was generally not available early enough to have influenced the shape of the first pandemic wave and it is likely that any future pandemic vaccine manufactured using current technology will also be available too late, at least in one hemisphere. SUMMARY: Border screening, school closure, widespread anti-viral prophylaxis and a pandemic-specific vaccine were unlikely to have been effective during a pandemic which was less severe than anticipated in the pandemic plans of many countries. These were cornerstones of the population-based public health response. Similar responses would be even less likely to be effective in a more severe pandemic. We agree with the recommendation from the World Health Organisation that pandemic preparedness plans need review.