Comparative Postmarket Safety Profile of Adjuvanted and High-Dose Influenza Vaccines in Individuals 65 Years or Older

IMPORTANCE Every year, influenza vaccines are administered to millions of people worldwide to reduce morbidity and mortality from influenza. As new vaccine formulations are increasingly used, monitoring and comparing safety, in addition to vaccine effectiveness, in target populations are essential. OBJECTIVE To assess the postmarketing safety profile of 2018 Southern Hemisphere influenza vaccines, particularly 2 new enhanced trivalent inactivated influenza vaccines: an adjuvanted trivalent inactivated influenza vaccine (aIIV3) and high-dose trivalent inactivated influenza vaccine (HD-IIV3), among Australian individuals 65 years or older. DESIGN, SETTING, AND PARTICIPANTS This cohort study used solicited short message service– based self-reported survey data on adverse events occurring within 3 to 5 days after receipt of an influenza vaccination. Participants included individuals 65 years or older who received routinely recommended influenza vaccines at 1 of 265 sentinel immunization sites, including primary care, hospital, and community-based clinics, participating in Australia’s AusVaxSafety active vaccine safety surveillance system from April 1 to August 31, 2018. Data were analyzed from September 1, 2018, to June 30, 2019. EXPOSURE Any licensed 2018 influenza vaccine administered in clinical practice. MAIN OUTCOMES AND MEASURES Rates (overall, by brand, and by concomitant vaccine receipt) of adverse events, including medical attendance as a proxy for serious adverse events. RESULTS Of 72013 individuals 65 years or older who received an influenza vaccine in 2018, 50134 individuals (69.6%) responded to the initial survey regarding adverse events experienced after vaccination (median [interquartile range] age, 71 [68-76] years; 27056 [54.0%] women). Most individuals received an enhanced trivalent inactivated influenza vaccine, including 28003 individuals (55.9%) who received aIIV3 and 19306 individuals (38.5%) who received HD-IIV3; 2208 CONCLUSIONS AND RELEVANCE The findings of this large-scale participant-based postmarketing assessmentofthesafetyof2newenhancedinfluenzavaccinesusedinindividuals65yearsorolder provide reassuring near-real-time and cumulative data to inform and support confidence in ongoing vaccine use. initial a second asking whether they sought medical attention for the adverse event as well as a link to a short online survey asking them to specify the adverse event. Solicited adverse events reports of any event (yes or no) and medical attention (our proxy for as defined by the Australian Therapeutic Goods Administration 36 or adverse events fever, injection site injection site or sleep pattern change, rigors,


Introduction
Globally, influenza kills hundreds of thousands of people each year, 1 disproportionally affecting older individuals. 2 Annual vaccination is the most effective public health measure available for influenza prevention, yet Australian and global coverage remain suboptimal. 3,4 Following a severe influenza season in 2017 during which more than 90% of 1100 recorded influenza-related deaths occurred among individuals 65 years or older, 5 the Australian National Immunisation Program (NIP) funded and preferentially recommended 2 new enhanced influenza vaccines for individuals 65 years or older: the non-adjuvanted high-dose trivalent inactivated influenza vaccine (TIIV), HD-IIV3, containing 60 μg of haemagglutinin per strain, and the adjuvanted TIIV, aIIV3, containing 15 μg of haemagglutinin per strain and MF59 oil in water emulsion adjuvant, rather than standard-dose quadrivalent inactivated influenza vaccine (QIIV). 6 These represented the first new formulations, other than standard-dose inactivated influenza vaccine, used under the Australian NIP. 7 Clinical trials and postlicensure studies have shown that both vaccines induce superior immunogenicity and offer improved effectiveness in older adults compared with standard TIIVs. [8][9][10][11][12][13][14] While safety analyses from clinical trials 8,9,15,16 have demonstrated increased injection site reaction rates for both enhanced vaccines compared with standard comparator TIIVs, reports of serious adverse events (SAEs) were uncommon. 9,[14][15][16] Because clinical trial safety data have inherent limitations, 17 postmarketing vaccine safety surveillance serves as a critical adjunct, demonstrating how a vaccine is tolerated in real-world use among large populations. This is particularly important for influenza vaccines. In anticipation of each Northern and Southern Hemisphere influenza season, influenza vaccine strain composition may vary to target the predominant circulating viral strains. 7,17,18 The variety of new influenza vaccine types available and manufacturing techniques used underpins the need to conduct additional postmarketing safety surveillance that can provide more detailed and timely brand-specific safety data than traditional spontaneous reporting systems can. To date, there are limited postmarketing safety data on high-dose and adjuvanted vaccines used in individuals 65 years or older. Surveillance that can monitor each season's new influenza vaccines to rapidly identify potential safety issues, including by brand, is recommended. 17 Safety incidents restricted to even 1 vaccine brand, such as the 2010 increase in severe febrile events in young Australian children, 19,20 can result in program suspension and setbacks to vaccine confidence and overall influenza vaccine coverage. 21,22 Numerous studies have demonstrated that concerns regarding influenza vaccine safety continue to contribute to hesitancy and poor vaccine uptake. 4,23,24 Improvements to Australia's vaccine safety surveillance following the 2010 safety incident and subsequent child influenza vaccination program suspension included creation of a national, active, sentinel surveillance system based on solicited participant-reported adverse events following immunization relayed via short message service (SMS). The AusVaxSafety vaccine safety surveillance system was established in 2014 and initially monitored influenza vaccine safety in children younger than 5 years, expanding to all ages and multiple vaccines from 2017. [25][26][27] Throughout the 2018 influenza vaccination period (April to August 2018), data were available daily, with weekly reporting of both adverse event rates (by age, brand, and dose) and automated Bayesian signal detection 25 ; no safety concerns were reported. Weekly analyses were reported to key immunization program stakeholders and the public via the AusVaxSafety. 28 Using 2018 cumulative surveillance data, this study assessed the comparative safety profiles of the 2 new seasonal influenza vaccines, HD-IIV3 and aIIV3, used in Australians 65 years or older.

Methods
AusVaxSafety and its surveillance tools operate nationally under human research ethical approval obtained from the Sydney Children's Hospital Network and the Royal Australian College of General Practitioners National Research and Evaluation Ethics Committee. Participant consent is on an opt-out basis. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Setting and Study Cohort
Australia's population is approximately 25 million people. 29 In 2018, AusVaxSafety captured data from more than 220 000 influenza vaccination encounters administered to individuals 6 months or older as routine clinical care at participating sentinel immunization sites, including general or family practices, hospitals, community-based immunization clinics, and Aboriginal Medical Services. In 2018, an estimated 11 million influenza vaccine doses 30 were distributed by the NIP; one-third of these were enhanced doses for adults 65 years or older. AusVaxSafety 2018 surveillance captured approximately 1.8% of the total population (3.9 million people 31 ) 65 years or older.
The NIP provides free influenza vaccines for all eligible Australian residents, based on age and risk factors for severe influenza. 32 In 2018, influenza vaccines were funded for individuals 65 years or older, most Indigenous people, pregnant women, and individuals with chronic underlying medical conditions. Other licensed vaccines, which not supplied under the NIP, are also included in AusVaxSafety postmarketing surveillance, although they are not generally administered to large numbers of people.
Individuals vaccinated at participating sites or their caregivers respond yes or no to an initial SMS, automatically sent 3 to 5 days after immunization by 1 of 2 surveillance tools, SmartVax 33 or Vaxtracker, 34 asking whether any adverse events occurred after vaccination. Although 2 surveillance tools contribute to AusVaxSafety data, SmartVax is the predominant source, currently providing 99% of AusVaxSafety data, including all data in this analysis. SmartVax 35 is installed at participating immunization sites and automatically extracts deidentified data on vaccination encounters from routinely used clinic software systems.
Respondents who reply yes to the initial question receive a second SMS asking whether they sought medical attention for the adverse event as well as a link to a short online survey asking them to specify the adverse event. Solicited adverse events include reports of any event (yes or no) and medical attention (our proxy for SAE as defined by the Australian Therapeutic Goods Administration 36 ) (yes or no). Solicited adverse events include fever, injection site pain, injection site swelling or redness, tiredness, headache, sleep pattern change, irritability, rash, vomiting, diarrhea, rigors, nonresponsiveness or loss of consciousness, and seizures. Unsolicited symptoms can be detailed in free text.
Our analysis included all adults 65 years or older at who received any seasonal influenza vaccine between April 1 to August 31, 2018, and replied within 7 days to the initial SMS sent via the SmartVax tool by their participating AusVaxSafety immunization site. Persons who received 2 vaccine doses during the study period (such as select immunocompromised individuals) may be represented by more than 1 record. 37

Outcomes
Descriptive variables for respondents were summarized, including sex, Aboriginal and/or Torres Strait Islander (hereafter, Indigenous) status, age, timing or season of vaccination, vaccine brand and type, and concomitant vaccine administration (defined as any additional vaccine received at the same visit as the influenza vaccine). Indigenous status, when recorded, was provided by the individual at the

Statistical Analysis
Rates of adverse events were summarized by brand and type for HD-IIV3 (Fluzone High-Dose

Study Cohort
From

Rates of Specific Adverse Events and Medical Attention by Vaccine Type
The most commonly reported solicited adverse event according to vaccine type were injection site  Table 3). For most solicited adverse events, rates associated with receipt of HD-IIV3 were higher than both those associated with aIIV3 or any QIIV receipt (  Table 3).

Rates of Any Adverse Event and Medical Attention by Concomitant Vaccination Status
Rates of adverse events were higher for individuals who received any concomitant vaccine compared  Table 4). For individuals whose concomitant vaccine was    method for quality postmarketing vaccine safety data. 17 To our knowledge, our system is the largest global postmarketing active vaccine safety surveillance system in terms of participant numbers.

Discussion
Our retrospective analysis included more than 50 000 individuals 65 years or older who received an influenza vaccine and responded to an SMS-based survey regarding adverse events experienced 3 to 5 days after vaccination. While near real-time safety monitoring in 2018 did not detect any safety signals, this end-of-season analysis found that individuals who received HD-IIV3 reported adverse events more commonly than those who received other influenza vaccines.
However, this difference was not large, and absolute reported rates were not high. Reports consisted predominantly of nonserious events and did not vary greatly among brands. When adjusted for potential confounders, the increased risk of any adverse event associated with HD-IIV3 compared with aIIV3 was small. Our adjusted model demonstrated that younger age groups were significantly less likely than older age groups to report any adverse event, while women were more likely than men to report adverse events. These were likely associated with circumstantial or behavioral factors, such as the increased likelihood of women being attentive to health care concerns. 39 Although individuals who received HD-IIV3 reported more injection site symptoms and fever, medical attention rates, our proxy for SAE, were low and similar for HD-IIV3 and aIIV3 at 0.3%. These empirical data demonstrated no unexpected burden on the health care system due to adverse events associated with influenza vaccines.
Randomized clinical trials of HD-IIV3 and aIIV3 have reported injection site pain in 36% of individuals who received HD-IIV3 (vs 24% of individuals who received standard TIIV) and 32% of individuals who received aIIV3 (vs 17% of individuals who received standard TIIV). 5,15,16 In comparison, adverse event rates reported via our system were lower than these expected ranges. We including lack of denominator, variable reporting lags, and biases that may be introduced by underreporting, stimulated reporting, or incomplete reporting. 41,42 However, in line with our results, VAERS demonstrated that injection site pain, swelling, and redness were more commonly reported by individuals who received HD-IIV3 compared with those who received aIIV3. 40 In contrast to passive systems like VAERS, our participant-based monitoring allows for direct comparison of adverse events occurring within the first week of vaccination, underpinned by denominator data consisting of doses administered (recorded by brand in clinic software). Our large sentinel population enables detection of even minor differences in adverse event rates.
Our analysis, like previous data we have reported, 25,28 demonstrated higher adverse event rates with receipt of a concomitant PPSV23. This outcome was observed for recipients of both enhanced vaccines. Increased local reactions associated with PPSV23, and in particular with revaccination, have been reported elsewhere. [43][44][45][46] Receipt of PPSV23 concomitantly with influenza vaccine was also independently associated with increased medical attention rates compared with receipt of influenza vaccine alone.

Limitations and Strengths
There are several limitations of our system and analysis. Although our system includes data specifying injection site arm, these data are currently not uniformly completed, and our ability to attribute a local reaction to a particular vaccine when more than 1 vaccine was received remains a limitation. Additionally, AusVaxSafety is designed to compile reports of adverse events that occur within days of vaccination and does not collect data on events occurring beyond this timeframe. The system in its current design does not detect very rare adverse events. In theory, given our large number of participants, we could identify very rare events for some vaccines or age groups. However, these unsolicited events would need to be detailed in free text by participants because they would not appear in our list of solicited events. Nevertheless, used in conjunction with Australia's spontaneous adverse event reporting system, the Adverse Events Management System database administered by the Therapeutic Goods Administration, our active surveillance enhances Australia's ability to potentially detect and investigate rare events.
Given the nature of active, participant-based surveillance, it is possible that some SAEs will go unreported if an individual is unable to report owing to the event or has died. Another expected limitation of adverse event surveillance is that not all events will be causally related to vaccination 47 ; adverse event rates may be associated with illnesses with similar outcomes, such as fever from intercurrent viral illness, which cannot be differentiated from causally related events. Furthermore, our data rely on self-or caregiver-report of outcomes not clinically verified by a health professional and may be less objective for some adverse events compared with clinician-based reporting. While we have attempted to adjust for potential biases by reporting more objective outcomes, such as health care utilization and fever, this remains a limitation. Nevertheless, understanding individual perceptions of adverse events is valuable, and quantifying self-reported adverse events provides real-world safety data that are a window into individual perception of the safety of widelyadministered vaccines.
Our study also has some strengths. Importantly, AusVaxSafety surveillance incorporates denominator data. Moreover, our system is timely and able to confirm the safety of each administered brand within weeks of the influenza vaccination program rollout. Since commencing influenza vaccine safety surveillance in 2014, our adverse event rates have, reassuringly, been stable and consistent across seasons. [25][26][27][28]48 In addition to its timeliness, AusVaxSafety is able to be adapted quickly to conduct surveillance for new vaccines, and the system's flexibility would facilitate its utility if a new pandemic vaccine were to be rolled out rapidly in the Australian population.
However, the essential strength of AusVaxSafety is its ability to enable clinicians to provide patients with a realistic portrait of adverse events that may occur after influenza vaccine receipt, based on adverse events reported by geographically and demographically similar people in near real time. This transparency, reported anecdotally by immunization stakeholders, including health care practitioners providing vaccine, empowers clinicians. We are currently evaluating the system to provide an objective assessment of this and to assess the extent to which this may influence decision-making and potentially result in greater confidence in, or uptake of, influenza and other vaccines.

Conclusions
The