Adverse events following HPV immunization in Australia: Establishment of a clinical network

ABSTRACT

Objective: To formalise a collaborative national Adverse Events Following Immunisation Clinical Assessment Network (AEFI-CAN) following the expansion of the Australian Human Papillomavirus (HPV) immunisation program to boys in 2013. Methods: AEFI-CAN linked state-based vaccine safety clinics and the Department of Health including the Therapeutic Goods Administration (TGA). Monthly teleconferences held to discuss HPV related cases. AEFI conditions of interest recorded in a centralised database. Results: Between 1^st January 2013 - 31^st October 2014, 118 HPV AEFI were documented, 56% in males. The median age was 13 y (range 12–16 years). The majority of AEFI reports were after dose 1 (59%). 76 of 118 (64%) AEFI were seen in a vaccine safety clinic: 62% in Victoria, NSW (16%), South Australia (9%) and Western Australia (8%). Eight TeleHealth consultations were undertaken. AEFI were categorised as: rash 24% of reports (n = 28), urticaria/angioedema 23% (n = 27), anaphylaxis 3% (n = 4). Syncope was also reported (n = 12, 10%) and other neurological events (n = 22, 19%). Conclusions: We demonstrated the advantages of a national network, providing a collaborative approach to AEFI review and management. The vaccine safety network has applicability to any vaccination program, and has potential to collaborate more broadly with regional pharmacovigilance partners such as New Zealand.

KEYWORDS:

• clinical network
• HPV
• safety
• vaccine

Introduction

Surveillance of adverse events following immunisation (AEFI) is an integral part of the safe implementation of an immunisation program.¹ Administration of vaccines to primarily healthy individuals means that community expectations for safety are high.

Surveillance for AEFI aims to detect rare, late-onset, unexpected or population-specific adverse events. AEFI surveillance therefore plays an important role in detecting vaccine associations and complications that occur at a lower frequency than detected in the pre-licensure trials. Background rates of conditions of interest for males at the introduction of the HPV vaccine in Victoria, Australia, were described, estimating the numbers of neurological, allergic and other events expected to occur due to temporal association alone.² A possible AEFI ‘signal’ is raised if the reported rate of adverse events is potentially higher than that which would be expected from these background rates. A vaccine safety signal may not establish a causal relationship and further investigation is required to demonstrate causality.³ In prelicensure trials of the quadrivalent HPV vaccine Gardasil™, serious adverse events occurred at similar rates to administration of placebo. Injection site pain, erythema and oedema were common, occurring more frequently in vaccine recipients versus placebo recipients.⁴

In Australia, the 4-valent HPV vaccine became part of the national immunisation program for school-aged females in 2007. A government-funded catch-up program for females aged 12–26 y also commenced in 2007. Males were included in the program in 2013, when the ongoing program was extended to boys aged 12–13 y and a 2 y catch-up for males aged 14–15 y commenced. The vaccine used in the program is the 4-valent HPV vaccine (Gardasil™), with a recommended 3-dose vaccine schedule at 0, 2 and 6-months from initial vaccination.

The aim of AEFI-CAN was to undertake enhanced passive surveillance and clinical assessment for serious AEFI in all Australian jurisdictions. Specific objectives included: (i) Facilitate consistent approaches to the clinical response and causality assessment for serious adverse events following HPV immunisation; (ii) enable accurate, standardised documentation of significant/unexpected HPV AEFI, including documenting outcomes and making decisions regarding further vaccination.

Results

From 1 January 2013 to 30 June 2014, comprehensive AEFI clinical details were obtained on 118 reports for 114 individuals. 76 (67%) patients were seen in a vaccine safety clinic: 62% in Victoria, 16% in New South Wales, 9% South Australia and 8% in Western Australia. One case, a serious AEFI (anaphylaxis), was reported in the Northern Territory and discussed at AEFI-CAN. No patients were reviewed in Australian Capital Territory or Tasmania. Eight TeleHealth consultations were undertaken: Victoria⁵ Western Australia.³

During 1 January 2013 – 30 June 2014, the TGA received 1201 suspected HPV AEFI notifications (656 male, 545 female).⁸ Thus 9.8% (118/1201) of AEFI reported as part of the HPV program were assessed by the AEFI-CAN network.

Of the 114 vaccinees evaluated, 56% were male (median age of 13 y (range 12–16 years)). The majority of AEFI reports were after HPV vaccine dose 1 (59%), with 34% post dose 2 and 7% following dose 3. The main AEFI categories were rash: 24% of reports (n = 28), allergy (urticaria/angioedema): 23% (n = 27) and anaphylaxis: 3% (n = 4). The possible allergic cases with more detailed information are outlined in Table 1. Neurological adverse events included syncope (n = 12, 10%) and other serious neurological events (n = 22, 19%). Neurological presentations included a case of Bells palsy and a complex tic disorder, neither was deemed causally vaccine related upon assessment. There were no reported cases of GBS or CRS. AEFI-CAN reports also included anxiety symptoms (4%) and somatic complaints (2%).

Table 1. Detailed description of possible allergic AEFI (n = 15/N = 31 [48%]).

Patient number	HPV vaccine dose (and concomitant vaccines)	Suspected hypersensitivity reaction	Onset of reaction (min)	Referral to allergy clinic	Reaction to next dose?	Management of reaction	Notes
1	First and second dose	Angioedema and pruritis and swelling of legs	Unknown	No	None	N/A	Report several months after reactions
2	First dose	Angioedema and urticarial rash on face	120	Yes	Yes- dysphagia and paraesthesia after 50 mins	Anti-histamine Referral to allergy clinic
3	First dose (+ Varilirix®)	Angioedema and urticaria	40	Yes	Yes- pruritis and rash	Anti-histamine Referral to allergy clinic
4	First dose	Angioedema and urticarial rash	540	Yes	N/A^*	N/A
5	Second dose	Dizziness, rash, angioedema	15	No	N/A	N/A
6	Second dose	Swollen face and eyes	480	No	None	N/A
7	First dose	Anaphylaxis Loss of consciousness then altered conscious state for 1 hr Stridor 1 dose adrenaline	2	Yes	N/A	N/A
8	First dose	Erythematous rash on both wrists. Pruritis and sore, slightly puffy eyes.	10	Yes	No reaction to second dose (first dose of Cervarix®), subsequent reaction below	N/A	Intradermal testing- No reaction to Gardasil® or Cervarix®
9	Third dose (second dose of Cervarix®)	Anaphylaxis- Pruritis of L shoulder and headache hypertension, tachycardia and cough.	8	N/A	N/A	Adrenaline Antihistamine
10	Second dose (+ Varilirix®)	Sneezing and red blotchy skin, progressing to urticaria and lip swelling.	10	Yes	N/A	N/A
11	Unknown	Urticarial rash	360	No	N/A	N/A
12	First dose (+ Varilirix®)	Angioedema	30	No	None	N/A
13	Second dose	Dysphagia, cough, chest tightness, angioedema, pruritis	225	Yes	N/A	N/A	Negative intradermal test to Gardasil™ but persistent pruritis and erythema
14	Unknown (+ Boostrix)	Urticaria	3 days	No	None	N/A
15	Third dose	Delayed hypersensitivity (urticarial rash, wheeze, diarrhoea)	120	No	N/A	N/A

* N/A- nil further doses administered.

Hospital Emergency Department review was undertaken by 26/114 patients (23%). All AEFI case reports were following the 4-valent Gardasil except for one case of anaphylaxis secondary to Cervarix™ (2v-HPV vaccine), as part of an expert allergy clinic vaccine challenge. Following clinic review, 31/76 patients (41%) received additional doses of HPV vaccine. Of those receiving further doses post the first AEFI, only recurrent adverse events occurred in the rash/ group (n = 3).(see Table 1)

Discussion

The AEFI-CAN HPV Pilot data was reassuring regarding safety of the vaccine in a new target population (12–15 y males). The uptake of the vaccine was over 70% for female and male secondary school students across Australia.⁹ The AEFI-CAN-HPV Pilot addressed the stated aims of the project. Monthly teleconferences served to facilitate discussion between state and territory clinicians and the TGA (as national regulator) regarding significant or unexpected HPV vaccine-related adverse events. This in turn led to improved clinical decision-making, and knowledge sharing among clinicians, states and territories, the Department of Health which assisted program roll out and community confidence in the program.

The main AEFI reports were rash and/or allergic reactions, including anaphylaxis cases. All AEFI cases were discussed at the monthly AEFI-CAN teleconferences, with formal allergy testing undertaken as required.(5, 7) TeleHealth consultations were utilised effectively both for communication between AEFI-CAN members and for consultations with families and patients. TeleHealth immunisation consultations saved travel time and assisted in education local clinicians. TeleHealth could potentially be expanded to assist in improving AEFI communication with healthcare workers and patients in rural and regional Australia.

Study limitations included delays in obtaining local ethics approval and incomplete data collection for some cases. There was a discrepancy in the overall number of passive AEFI reports by jurisdictions. Both Victoria (SAEFVIC) and Western Australia (WAVVS) have a well established integrated clinical and surveillance system. New South Wales and South Australia have long-standing vaccine safety clinics in their tertiary pediatric centers. Smaller jurisdictions (ACT and Northern Territory) had limited administrative and clinical resources to facilitate the clinical assessment of patients with potential AEFI. The clinicians from these jurisdictions had often not previously seen AEFI cases and there was no established referral pathway. In the case of Tasmania, AEFI reports were forwarded directly to the TGA, so individual cases were hard to identify as the TGA only collects de-identified data. Queensland did not get ethics approval in time for inclusion in the study reporting.

Although 41% of AEFI-CAN subjects received subsequent doses, a number elected not to have further vaccines, including those with possible allergic reactions (see Table 1), some of which were with the 3^rd and final HPV vaccine dose. Importantly very few recurrent AEFI were reported. Reasons for not completing the HPV vaccine 3-dose course is important. The change to a 2-dose HPV vaccine schedule in the future may impact on the proportion of AEFI patients receiving all of the recommended doses. Insufficient data was available to apply Brighton criteria to all the AEFI of interest. This will be important in collation of AEFI-CAN data in the future. Feedback from consumers and healthcare workers is important as we aim to improve our vaccine safety clinical services.

More data is required on what triggered a clinic review in each jurisdiction, with varying referral pathways/ procedures and seriousness of the AEFI likely to be contributing factors. While the pilot highlighted the difficulty in establishing a truly national network within the Australian context, significant improvements were made in relation to networking between those states with existing vaccine safety clinics and processes for monitoring and following up on AEFI.

AEFI-CAN members are interested in expanding local vaccine safety collaborations with New Zealand and other countries in the Asia-Pacific. Drawing on expertise from the World Health Organization and Brighton Collaboration could aid in this process, particularly the detection and management of serious AEFI cases.

Methods

AEFI in Australia that are considered serious are referred for an expert opinion at a tertiary vaccine safety clinic. These clinics are co-ordinated by pediatricians with expertise in the field and rely on passive referrals from a primary healthcare physician. The process for referral varies by each Australian jurisdiction (state or territory). Each clinic appointment includes a feedback to the referrer, vaccine/family and other healthcare workers involved, detailing the outcome of the visit and future vaccination plan.

In attempt to coordinate these activities we formed a national body called AEFI-CAN [Adverse events following immunisation: clinical assessment network]. It comprised a representative from Australian States and Territories, plus the Therapeutic Goods Administration (TGA). An observer from New Zealand pharmacovigilance also attended the teleconferences. The initiative was coordinated by SAEFVIC, Victoria.¹, with funding support from the Australian Government Department of Health. Each site obtained ethics approval, identified cases and entered data into a Redcap™ database.

TeleHealth consultations were undertaken for patients living outside metropolitan areas who required expert review. Data on AEFI were collated and assessed at monthly teleconferences and detailed case record forms (CRF) were provided for 5 AEFI of interest: rash, anaphylaxis, Gullian-Barré Syndrome (GBS), syncope and complex regional pain syndrome (CRPS).(5, 6) These CRFs were selected by the authors following consultation with the Department of Health and were expected AEFI following the rollout of the female HPV program in 2007. The CRFs were based on Brighton collaboration criteria and were previously used in AEFI-related publications.⁷ Data was collected retrospectively (1st January- 1^st August 2013) and prospectively (2^nd August 2013- 30^th October 2014). Quarterly reports were provided to the Department of Health, Canberra.

Conclusions

A comprehensive system for detecting adverse events is important for the safe and efficacious implementation of a national immunisation program. AEFI-CAN has demonstrated the advantages of a national clinical assessment network to provide a collaborative approach to AEFI detection and management. It provided a regular forum for clinical discussion and planning for individual patients following serious or unexpected adverse events following immunisation. The AEFI-CAN Network has been utilised for the HPV vaccine program but has potential broader application to all vaccines on the Australian National Immunisaton Program.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

AEFI-CAN thank the Australian Government Department of Health for funding this project. The authors acknowledge Annette Alafaci (Research Assistant, SAEFVIC, Vic) for collating the AEFI-CAN data, as well as all other members of the AEFI-CAN team: Chris Blyth, Peter Richmond, Patricia Cuthbert (WAVSS, WA); Sean Beggs (Royal Hobart Hospital, Tas); Asha Bowen (Royal Darwin Hospital, NT); Kathy Cannings, Karen Orr (Westmead Children's Hospital, NSW); Mary Walker (Women's and Children's Health Network, SA); Margie Danchin, Kirsten Perrett (SAEFVIC, Vic); Michael Nissen, Leanne Philips (Brisbane Royal Children's Hospital, Qld); Graham Reynolds (Canberra Hospital, ACT).

Funding

The project was funded by the Australian Government Department of Health.