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Thrombotic events following the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) in Aotearoa New Zealand: A self-controlled case series study

  • Author Footnotes
    1 Joint first authors.
    Muireann Walton
    Footnotes
    1 Joint first authors.
    Affiliations
    Ministry of Health New Zealand, Wellington, New Zealand

    Te Whatu Ora, Health New Zealand, New Zealand
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  • Author Footnotes
    1 Joint first authors.
    Robert Tomkies
    Footnotes
    1 Joint first authors.
    Affiliations
    Ministry of Health New Zealand, Wellington, New Zealand
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  • Thomas Teunissen
    Affiliations
    Ministry of Health New Zealand, Wellington, New Zealand
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  • Author Footnotes
    2 Address: Science Centre - MATHPHYSIC - Bldg 303, 38 Princes St, Auckland 1010, New Zealand.
    Thomas Lumley
    Footnotes
    2 Address: Science Centre - MATHPHYSIC - Bldg 303, 38 Princes St, Auckland 1010, New Zealand.
    Affiliations
    Chair in Biostatistics, Faculty of Science, Statistics, University of Auckland, New Zealand
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  • Timothy Hanlon
    Correspondence
    Corresponding author at: The Vaccine Safety Surveillance and Research Group, National Immunisation Programme, Te Whatu Ora Health New Zealand, 133 Molesworth Street, Wellington 6011, New Zealand.
    Affiliations
    Ministry of Health New Zealand, Wellington, New Zealand

    Te Whatu Ora, Health New Zealand, New Zealand
    Search for articles by this author
  • Author Footnotes
    1 Joint first authors.
    2 Address: Science Centre - MATHPHYSIC - Bldg 303, 38 Princes St, Auckland 1010, New Zealand.
Published:December 27, 2022DOI:https://doi.org/10.1016/j.thromres.2022.12.012

      Highlights

      • Research has shown an association between thrombosis, SARS-CoV-2 infection, and adenovirus-based COVID-19 vaccines.
      • The risk of specific adverse thrombotic events following vaccination with BNT162b2 was evaluated.
      • BNT162b2 vaccination was not found to be associated with an increased risk of thrombosis in New Zealand.

      Abstract

      Background

      An association between thrombotic events and SARS-CoV-2 infection and the adenovirus-based COVID-19 vaccines has been established, leading to concern over the risk of thrombosis after BNT162b2 COVID-19 vaccination.

      Objectives

      To evaluate the risk of arterial thrombosis, cerebral venous thrombosis (CVT), splanchnic thrombosis, and venous thromboembolism (VTE) following BNT162b2 vaccination in New Zealand.

      Methods

      This was a self-controlled case series using national hospitalisation and immunisation records to calculate incidence rate ratios (IRR). The study population included individuals aged ≥12 years, unvaccinated, or vaccinated with BNT162b2, who were hospitalised with one of the thrombotic events of interest from 19 February 2021 through 19 February 2022. The risk period was 0–21 days after receiving a primary or booster dose of BNT162b2.

      Results

      6039 individuals were hospitalised with one of the thrombotic events examined, including 5127 with VTE, 605 with arterial thrombosis, 272 with splanchnic thrombosis, and 35 with CVT. The proportion of individuals vaccinated with at least one dose of BNT162b2 ranged from 82.7 % to 91.4 %. Compared with the control unexposed period, the IRR (95 % CI) of VTE, arterial thrombosis, splanchnic thrombosis, and CVT were 0.87 (0.76–1.00), 0.73 (0.56–0.95), 0.71 (0.43–1.16), and 0.87 (0.31–2.50) in the 21 days after BNT162b2 vaccination, respectively. There was no statistically significant increased risk of thrombosis following BNT162b2 in different ethnic groups in New Zealand.

      Conclusion

      The BNT162b2 vaccine was not found to be associated with thrombosis in the general population or different ethnic groups in New Zealand, providing reassurance for the safety of the BNT162b2 vaccine.

      Keywords

      1. Introduction

      Thrombotic events have emerged as a known and serious complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection [
      • Ho F.K.
      • Man K.K.
      • Toshner M.
      • et al.
      Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort.
      ,
      • Malas M.B.
      • Naazie I.N.
      • Elsayed N.
      • et al.
      Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis.
      ,
      • Moschonas I.C.
      • Tselepis A.D.
      SARS-CoV-2 infection and thrombotic complications: a narrative review.
      ]. An association between thrombosis and the adenovirus based COVID-19 vaccines; ChAdOx1-S nCoV-19 (Oxford-AstraZeneca/Vaxzevria) and Ad26.COV2.S (Johnson & Johnson's Janssen/Jcovden) has also been established, including thrombotic events with and without thrombocytopenia [
      • Andrews N.J.
      • Stowe J.
      • Ramsay M.E.
      • Miller E.
      Risk of venous thrombotic events and thrombocytopenia in sequential time periods after ChAdOx1 and BNT162b2 COVID-19 vaccines: a national cohort study in England.
      ,
      • Simpson C.R.
      • Shi T.
      • Vasileiou E.
      • et al.
      First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
      ,
      • Hippisley-Cox J.
      • Patone M.
      • Mei X.W.
      • et al.
      Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.
      ,
      • Medsafe
      New Zealand Data Sheet. Vaxzevria. Version 040422.
      ,
      European Medicines Agency
      Jcvden (previously COVID-19 vaccine Janssen) : EPAR- Product Information.
      ]. As a result, there has been increased public and regulatory concern over the risk of thrombosis following the mRNA COVID-19 vaccines, such as the BNT162b2 mRNA vaccine (Pfizer-BioNTech/Comirnaty, hereafter BNT162b2). New Zealand's COVID-19 Vaccine and Immunisation programme began vaccinations in February 2021 and almost exclusively uses the BNT162b2 vaccine []. Although the Pfizer-BioNTech phase III clinical trials [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ] and subsequent international observational studies [
      • Simpson C.R.
      • Shi T.
      • Vasileiou E.
      • et al.
      First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
      ,
      • Abbattista M.
      • Martinelli I.
      • Peyvandi F.
      Comparison of adverse drug reactions among four COVID-19 vaccines in Europe using the EudraVigilance database: thrombosis at unusual sites.
      ,
      • Hviid A.
      • Hansen J.V.
      • Thiesson E.M.
      • Wohlfahrt J.
      Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: a retrospective cohort study.
      ,
      • Barda N.
      • Dagan N.
      • Ben-Shlomo Y.
      • et al.
      Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.
      ,
      • Klein N.P.
      • Lewis N.
      • Goddard K.
      • et al.
      Surveillance for adverse events after COVID-19 mRNA vaccination.
      ,
      • Houghton D.E.
      • Wysokinski W.
      • Casanegra A.I.
      • et al.
      Risk of venous thromboembolism after COVID-19 vaccination.
      ] have not found an association between the two, thrombotic events have been reported following the BNT162b2 vaccine through the New Zealand spontaneous reporting (passive surveillance) system [
      • Medsafe
      COVID-19. Safety Monitoring. Overview of Vaccine Reports. Safety Report #43- 30 April 2022.
      ] and internationally [
      • Alhashim A.
      • Hadhiah K.
      Extensive cerebral venous sinus thrombosis (CVST) after the first dose of Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine without thrombotic thrombocytopenia syndrome (TTS) in a healthy woman.
      ,
      • Tobaiqy M.
      • MacLure K.
      • Elkout H.
      • Stewart D.
      Thrombotic adverse events reported for moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines: comparison of occurrence and clinical outcomes in the EudraVigilance database.
      ]. Moreover, a self-controlled case series (SCCS) study in England reported an increased risk of cerebral venous thrombosis (CVT) and arterial thrombosis during the 15 to 21 days after the first dose of the BNT162b2 vaccine [
      • Hippisley-Cox J.
      • Patone M.
      • Mei X.W.
      • et al.
      Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.
      ].
      Rigorous post-marketing surveillance of the BNT162b2 vaccine is therefore needed to understand the risk of thrombosis following immunisation in the population, especially as concern around adverse events is a leading contributor to vaccine hesitancy [
      • Prickett K.C.
      • Habibi H.
      • Carr P.A.
      COVID-19 vaccine hesitancy and acceptance in a cohort of diverse new zealanders.
      ]. It is particularly important in New Zealand, as the country has a unique demographic, consisting of three main minority ethnic groups, Māori (indigenous New Zealanders) (16.5 % of the population), Pacific peoples (Pacific islanders living in New Zealand) (8.1 % of the population), and Asian (15.1 % of the population), alongside the majority group, New Zealand Europeans (70.2 % of the population) [
      • StatsNZ
      Taturanga Aotearoa. New Zealand's population reflects growing diversity.
      ]. New Zealand's Māori and Pacific peoples were not included in the Pfizer-BioNTech phase III clinical trials [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ] or any subsequent international post-licensure COVID-19 vaccine studies. Furthermore, Māori and Pacific peoples are at greater risk of hospitalisation and morbidity from COVID-19 [
      • Steyn N.
      • Binny R.N.
      • Hannah K.
      • et al.
      Māori and Pacific People in New Zealand Have Higher Risk of Hospitalisation for COVID-19.
      ,
      • Steyn N.
      • Binny R.N.
      • Hannah K.
      • et al.
      Estimated inequities in COVID-19 infection fatality rates by ethnicity for aotearoa New Zealand.
      ], and persistent inequities in health experiences, access, and outcomes has been observed in these groups, including access to COVID-19 vaccinations [
      • Graham R.
      • Masters-Awatere B.
      Experiences of Māori of aotearoa New Zealand's public health system: a systematic review of two decades of published qualitative research.
      ,
      • Whitehead J.
      • Scott N.
      • Atatoa-Carr P.
      • Lawrenson R.
      Will access to COVID-19 vaccine in aotearoa be equitable for priority populations?.
      ,
      • Marriott L.
      • Sim D.
      Indicators of inequality for Maori and Pacific people.
      ]. Vaccine coverage has also been traditionally lower for Māori and Pacific peoples compared to other ethnic groups in New Zealand [
      • O’Hallahan J.
      • McNicholas A.
      • Galloway Y.
      • et al.
      Delivering a safe and effective strain-specific vaccine to control an epidemic of group B meningococcal disease.
      ,
      • Paterson J.
      • Schluter P.
      • Percival T.
      • Carter S.
      Immunisation of a cohort Pacific children living in New Zealand over the first 2 years of life.
      ,
      • Pointon L.
      • Howe A.S.
      • Hobbs M.
      • et al.
      Evidence of suboptimal maternal vaccination coverage in pregnant New Zealand women and increasing inequity over time: a nationwide retrospective cohort study.
      ].
      New Zealand is uniquely placed to carry out pharmacovigilance of COVID-19 vaccines in the real-world. Throughout the first year of vaccinations, the country had low rates of SARS-CoV-2 in the community, largely due to the government's commitment to an elimination strategy [
      • Baker M.G.
      • Wilson N.
      • Anglemyer A.
      Successful elimination of Covid-19 transmission in New Zealand.
      ]. As a result, approximately 95.5 % of the total eligible population had received at least one dose of the BNT162b2 vaccine prior to the widespread community outbreak of SARS-CoV-2 from late February 2022 []. Given that thrombosis is also associated with SARS-CoV-2 infection, high rates of undetected infection seen in many countries throughout the pandemic can confound vaccine safety studies. New Zealand therefore provides an ideal setting to study the relationship between thrombotic events and the BNT162b2 vaccine. Given the conflicting information in the literature, the concern from the public and regulatory authorities, and the need to understand the association between thrombotic events and the BNT162b2 vaccine in the New Zealand population, we conducted a population-based self-controlled case series (SCCS) study using national electronic health records.

      2. Methods

      2.1 Study design

      We carried out an SCCS study to compare the incidence of an event of interest in an exposed risk period (e.g., post-vaccination) to all other “unexposed” periods (the control period) within individuals [
      • Whitaker H.J.
      • Farrington C.P.
      • Spiessens B.
      • Musonda P.
      Tutorial in biostatistics: the self-controlled case series method.
      ,
      • Farrington C.
      Relative incidence estimation from case series for vaccine safety evaluation.
      ,
      • Ghebremichael-Weldeselassie Y.
      • Jabagi M.J.
      • Botton J.
      • et al.
      A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
      ]. The observation period began with the start of COVID-19 vaccinations in New Zealand on 19 February 2021 through 19 February 2022. The study population comprised all individuals, aged 12 years and older, unvaccinated, or vaccinated with the BNT162b2 vaccine who were hospitalised with one of the prespecified thrombotic events during the observation period. We excluded individuals who tested positive for SARS-CoV-2 infection 31 days prior to the event to remove any potential bias associated with the increased risk of thrombosis following COVID-19 [
      • Ho F.K.
      • Man K.K.
      • Toshner M.
      • et al.
      Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort.
      ]. Participants vaccinated with a COVID-19 vaccine other than the BNT162b2 vaccine were also excluded.

      2.2 Prespecified events

      We identified four prespecified thrombotic events for inclusion in this study: arterial thrombosis, cerebral venous thrombosis (CVT), splanchnic thrombosis, and venous thromboembolism (VTE), based on their identification as an adverse event of special interest (AESI) for the BNT162b2 vaccine COVID-19 vaccine [
      Brighton Collaboration
      Safety Platform for Emergency VACcines (SPEAC). Priority List of Adverse Events of Special Interest: COVID-19. V2.0.
      ]. We used International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD-10-AM) diagnosis codes to identify these events (Supplementary Table S1).

      2.3 Data sources

      We used a de-identified dataset, prepared by the Data and Analytics team within the Ministry of Health New Zealand. Prespecified events were identified from the National Minimum Data Set (NMDS), a national collection of all public and most private hospital discharges, including coded clinical data for inpatients and day patients [
      Ministry of Health New Zealand
      Health Statistics. National Minimum Dataset (hospital events).
      ]. All New Zealand citizens (including Cook Islands, Niue, or Tokelau), residents, or individuals with a work visa that is valid for two years or more, are eligible for publicly funded health and disability services [
      Ministry of Health New Zealand
      NZ Health System. Guide to eligibility for publicly funded health services.
      ]. The National Health Index (NHI) number is provided to each person who uses these services. The Data and Analytics team used the NHI number to link the hospitalisation information with BNT162b2 vaccination records in the national COVID Immunisation Register (CIR), a database of all COVID-19 vaccination information in New Zealand []. The CIR also provides information on the mortality status of vaccinated individuals as it is linked via the NHI number to the Health Service Utilisation (HSU), which provides estimates of the New Zealand population. The Pandemic Minimum Dataset, New Zealand's national notifiable disease repository for COVID-19, was used to check if an individual tested positive for SARS-CoV-2 infection during the observation period.

      2.4 Exposures

      The BNT162b2 vaccine is normally administered as a two dose primary series (for some people the primary course can be >2 doses), with the government recommended dosing interval ranging from three to six weeks at different stages of the vaccine rollout in New Zealand [
      COVID-19 GOVT NZ
      Time between doses of COVID-19 Vaccine extended- media release 12 Aug 2021.
      , ,
      COVID-19 GOVT NZ
      Latest news- Booster vaccine available from end of November – statement released 15 Nov 2021.
      ]. Booster doses were offered from November 2021. These were provisionally approved by Medsafe, New Zealand's medicines and medical devices safety authority, for use six months after the primary course, however programme changes reduced this interval to four and then three months [
      Ministry of Health New Zealand
      NZ Health System. Guide to eligibility for publicly funded health services.
      ]. We classified an individual as exposed after receiving either a first, second, or booster dose of the vaccine within a prespecified risk window during the study observation period. Individuals who received >2 doses as their primary vaccination course were excluded from the analyses. We combined our analyses for all exposure periods as the vaccine effect was the same for each dose i.e., the risk was non dose dependent. The risk period for all events was set as 0–21 days after the first, second, and booster vaccine doses. This is in line with the approved 3-week interval between the two primary doses [] and a generally accepted risk interval for these types of events following COVID-19 vaccination [
      • Klein N.P.
      • Lewis N.
      • Goddard K.
      • et al.
      Surveillance for adverse events after COVID-19 mRNA vaccination.
      ]. We also tested the significance of implementing multiple risk intervals (0–6, 7–13, 14–21 days).

      2.5 Statistical analysis

      We conducted our primary analysis using the SCCS package constructed by Weldeselassie and Farrington [] within the R statistical package [
      COVID-19 GOVT NZ
      Latest news- Booster vaccine available from end of November – statement released 15 Nov 2021.
      ]. The SCCS models were fitted with a conditional Poisson regression model to estimate incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) for the thrombotic events within the exposed risk period compared to the control (unexposed) periods. Since this method involves within person comparisons, time-invariant confounders such as sex, ethnicity, and underlying health conditions, are automatically adjusted for [
      • Farrington C.
      • Whitaker H.
      Semiparametric analysis of case series data.
      ].We tested the significance of the time-invariant effect modifiers; ethnicity, gender, and age group on the model. We compensated for time varying confounders by adjusting for seasonality (4 seasons in the New Zealand calendar year) as the risk of a thrombotic event may follow a seasonal pattern [
      • Salehi G.
      • Sarraf P.
      • Fatehi F.
      Cerebral venous sinus thrombosis may follow a seasonal pattern.
      ,
      • Gallerani M.
      • Boari B.
      • De Toma D.
      • et al.
      Seasonal variation in the occurrence of deep vein thrombosis.
      ,
      • Lindqvist P.
      • Epstein E.
      • Olsson H.
      Does an active sun exposure habit lower the risk of venous thrombotic events? AD-lightful hypothesis.
      ]. Only the summer boundaries were implemented for CVT due to the scarcity of events. We also performed subgroup analyses to estimate the IRRs in different ethnic groups in New Zealand.

      2.6 Sensitivity analyses

      The standard SCCS model carries several assumptions, one of which is that events should arise independently within individuals [
      • Whitaker H.J.
      • Farrington C.P.
      • Spiessens B.
      • Musonda P.
      Tutorial in biostatistics: the self-controlled case series method.
      ]. This was tested using the Fleming-Harrington cumulative hazard plot. Only the first hospitalisation event was included in the model if this assumption was violated. Another assumption is that the occurrence of an event does not influence the probability of exposure [
      • Whitaker H.J.
      • Farrington C.P.
      • Spiessens B.
      • Musonda P.
      Tutorial in biostatistics: the self-controlled case series method.
      ]. To test this, we plotted a histogram of the time between vaccination and the occurrence of an event to determine whether the occurrence of a thrombotic event affected the timing of exposures e.g., results in an individual delaying or cancelling vaccination (the healthy vaccine bias). We introduced a pre-exposure risk period to compensate for any delays in vaccination and tested the significance of the event-dependent exposures on the model. We varied the length of the pre-exposure periods, between 2 and 42 days, and examined the impact on the relative incidence in both the pre-exposure and risk periods. If the event dependent exposure was not compensated for i.e., the delay in vaccination was prolonged, we implemented an extension of the SCCS method: the SCCS model for event-dependent exposures [
      • Farrington C.P.
      • Whitaker H.J.
      • Hocine M.N.
      Case series analysis for censored, perturbed, or curtailed post-event exposures.
      ,
      • Farrington P.
      • Whitaker H.
      • Weldeselassie Y.G.
      Self-controlled Case Series Studies:A Modelling Guide With R.
      ]. This model assumes that after every event, vaccination can be delayed or cancelled in an unspecified manner. As such, only exposures preceding the event were included in this model. We applied the modified SCCS for event dependent exposures using the R function “eventdepenexp” in the R-package “SCCS” [
      • Farrington P.
      • Whitaker H.
      • Weldeselassie Y.G.
      Self-controlled Case Series Studies:A Modelling Guide With R.
      ].
      The other form of event-dependence is when an event is associated with or is a death. In the standard SCCS model, deaths censor the observation period which violates the assumption that events should be independent of the observation period (event-dependent observation) [
      • Whitaker H.J.
      • Farrington C.P.
      • Spiessens B.
      • Musonda P.
      Tutorial in biostatistics: the self-controlled case series method.
      ]. Deaths caused by an event complicate the model but can provide useful information about the timing of the event. To investigate, we plotted a histogram of the data to visualise if there was event clustering at the end of the observation period and calculated the number of deaths that occurred after each event. We examined the significance of this on the SCCS model. If we observed both event dependent observations and an association between death and the events of interest (event dependent exposures), we implemented a recently proposed modification to the SCCS method [
      • Ghebremichael-Weldeselassie Y.
      • Jabagi M.J.
      • Botton J.
      • et al.
      A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
      ]. This method was developed specifically to compensate for both event-dependent exposures and high-event related mortality associated with some AESI following COVID-19 vaccinations. The model assumes that all deaths are related to the events observed and uses the planned end of observation rather than the date of death as the end of the observation period.

      2.7 Ethics approval

      This observational study did not require informed consent since we used deidentified data to conduct our analyses. As such, we received an exemption from the Health and Disability Ethics Committee (HDEC) of New Zealand (Reference #: 11950).

      3. Results

      3.1 Patient demographics

      The demographics of all individuals, aged 12 years or older, hospitalised with one of the prespecified thrombotic events from the 19 February 2021 through to 19 February 2022 are presented in Table 1. A total of 6039 individuals were identified, including 5127 (84.9 %) with a hospital diagnosis of VTE, 605 (10.0 %) with arterial thrombosis, 272 (4.5 %) with splanchnic thrombosis, and 35 (0.6 %) with CVT. There were 4439 (86.6 %) of 5127 individuals diagnosed with VTE, 520 (86.0 %) of 605 individuals diagnosed with arterial thrombosis, 225 (82.7 %) of 272 diagnosed with splanchnic thrombosis and 32 (91.4 %) of 35 individuals diagnosed with CVT that received at least one dose of the BNT162b2 vaccine.
      Table 1Baseline demographics of 6039 individuals hospitalised with a diagnosis of one of the prespecified thrombotic events, 19 February 2021 through 19 February 2022, New Zealand.
      Arterial thrombosis (%)Cerebral venous thrombosis (%)Splanchnic thrombosis (%)Venous thromboembolism (%)
      Diagnosed605 (10.0)35 (0.6)272 (4.5)5127 (84.9)
      Deaths119 (19.7)≤6
      Events with fewer than six occurrences have been suppressed for privacy reasons.
      71 (26.1)980 (19.1)
      Vaccinated with ≥1 dose of the vaccine520 (86.0)32 (91.4)225 (82.7)4439 (86.6)
      Modal age group76–10146–5566–7576–103
      SexMale332 (54.9)15 (42.9)162 (59.6)2510 (49.0)
      Female273 (45.1)20 (57.1)110 (40.4)2617 (51.0)
      EthnicityMāori and Pacific118 (19.5)≤657 (21.0)868 (16.9)
      NZ European, Asian, and other457 (75.5)21 (60.0)186 (68.4)3942 (76.9)
      Unknown30 (5.0)8 (22.9)29 (10.7)317 (6.2)
      a Events with fewer than six occurrences have been suppressed for privacy reasons.
      As of 19 February 2022, approximately 95.5 % of the eligible population in New Zealand (or 4,685,351 individuals), aged 12 years or older, had received at least one dose of the BNT162b2 vaccine. This equates to 86.0 % (or 490,851 individuals) of Māori, 88.2 % (or 252,881 individuals) of Pacific Peoples, 89.9 % (or 2,457,182 individuals) of NZ European and 89.9 % (or 538,175 individuals) of Asian, aged 12 years and older, having received at least one dose of the vaccine during the study period.

      3.2 Association between thrombotic events and the BNT162b2 vaccine

      Compared with the control, non-exposure period, the IRR (95 % CI) of VTE, arterial thrombosis, splanchnic thrombosis, and CVT were 0.87 (0.76–1.00), 0.73 (0.56–0.95), 0.71 (0.43–1.16), and 0.87 (0.31–2.50), respectively, in the 21 days following either the first, second or booster dose of the BNT162b2 vaccine in the general New Zealand population (Table 2 and Fig. 1). The IRR (95 % CI) of VTE, arterial thrombosis, and splanchnic thrombosis in the Māori and Pacific subgroup were 0.85(0.66–1.10), 1.27 (0.58–2.75), and 0.55 (0.17–1.77), respectively. The IRR (95 % CI) of CVT could not be calculated in this subgroup as there were too few events observed. The IRR (95 % CI) of VTE, arterial thrombosis, splanchnic thrombosis and CVT in the New Zealand European, Asian, and other subgroup were 0.85 (0.73–0.99), 0.55 (0.39–0.78), 0.73 (0.42–1.26), and 1.10 (0.35–2.93).
      Table 2Incidence rate ratios (95 % confidence intervals) of the prespecified thrombotic events in the 0–21-day risk period after exposure to the first, second or booster dose of the BNT162b2 vaccine in the general population and different ethnic groups in New Zealand, 19 February 2021 through 19 February 2022.
      OutcomeNo. of eventsIncidence rate ratio
      IRRs were calculated using Poisson regression and adjusted for seasonality.
      (95 % CI)
      Arterial thrombosis
      General population (all groups)Baseline605
      0–21 days650.73 (0.56 to 0.95)
      Māori and PacificBaseline118
      0–21 days81.27 (0.58 to 2.75)
      European NZ, Asian, and otherBaseline662
      0–21 days540.55 (0.39 to 0.78)
      Cerebral venous thrombosis
      General population (all groups)Baseline35
      0–21 days≤6
      Events with fewer than six occurrences have been suppressed for privacy reasons.
      0.87 (0.31 to 2.50)
      Māori and PacificBaseline≤6
      0–21 days
      The IRR was not calculated as there were too few events observed.
      European NZ, Asian, and otherBaseline21
      0–21 days≤61.01 (0.35 to 2.93)
      Splanchnic thrombosis
      General population (all groups)Baseline272
      0–21 days260.71 (0.43 to 1.16)
      Māori and PacificBaseline57
      0–21 days≤60.55 (0.17 to 1.77)
      European NZ, Asian, and otherBaseline215
      0–21 days230.73 (0.42 to 1.26)
      Venous thromboembolism
      General population (all groups)Baseline5127
      0–21 days6410.87 (0.76 to 1.00)
      Māori and PacificBaseline1113
      0–21 days1070.85 (0.66 to 1.10)
      European NZ, Asian, and otherBaseline4259
      0–21 days5340.85 (0.73 to 0.99)
      Note: Only the first event experienced by an individual is included.
      a IRRs were calculated using Poisson regression and adjusted for seasonality.
      b Events with fewer than six occurrences have been suppressed for privacy reasons.
      c The IRR was not calculated as there were too few events observed.
      Fig. 1
      Fig. 1Incidence rate ratios (95 % CI) of the prespecified thrombotic events in the 0–21 days after exposure to the first, second or third dose of the BNT162b2 vaccine in the general population (all ethnic groups) and different ethnic groups in New Zealand, 19 February 2021 through 19 February 2022. Note: The IRR of CVT in the Māori and Pacific subgroup was not calculated as there were too few events observed.

      3.3 Sensitivity analyses

      Table 3 presents the significance (p-value) of the effect modifiers (ethnicity, gender, and age), seasonal effect and the effect of the SCCS assumptions on the analysis. Each of the effect modifiers returned non-significant effects for all outcomes. There was a seasonal effect present for all thrombotic events except CVT. The number of thrombotic events observed in each season is outlined in Supplementary Table S2. For all outcomes, the lowest proportion of events were diagnosed in a hospital setting during the summer months in New Zealand (November 2021 through February 2022).
      Table 3The significance (p-value) of the effect modifiers, seasonal effect and SCCS assumptions on the analyses, and the final model configurations utilised to calculate the incidence rate ratios for each thrombotic event.
      Arterial thrombosisCerebral venous thrombosisSplanchnic thrombosisVenous thromboembolism
      Seasonal effect0.0100.8970.003<0.001
      Dose dependence0.5120.3460.6500.049
      Age effect modifier0.0770.3190.1370.470
      Ethnicity effect modifier0.8790.2950.5040.639
      Gender effect modifier0.1070.4280.2300.493
      Event dependent exposure<0.0010.0750.010<0.001
      Event dependent count<0.0010.067<0.001<0.001
      Event dependent impact0.160
      There were too few counts to calculate this number.
      0.329<0.001
      Final model implementedEvent dependent exposure model
      Event dependent exposure model developed by Farrington et al. [45,46].
      Standard SCCS modelEvent dependent exposure modelAdaption to the event dependent exposure model for high event-related mortality
      Adaption to the event dependent exposure model for high event-related mortality developed by Ghebremichael-Weldeselassie et al. [33].
      a There were too few counts to calculate this number.
      b Event dependent exposure model developed by Farrington et al.
      • Farrington C.P.
      • Whitaker H.J.
      • Hocine M.N.
      Case series analysis for censored, perturbed, or curtailed post-event exposures.
      ,
      • Farrington P.
      • Whitaker H.
      • Weldeselassie Y.G.
      Self-controlled Case Series Studies:A Modelling Guide With R.
      .
      c Adaption to the event dependent exposure model for high event-related mortality developed by Ghebremichael-Weldeselassie et al.
      • Ghebremichael-Weldeselassie Y.
      • Jabagi M.J.
      • Botton J.
      • et al.
      A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
      .
      There was a clustering of events (event dependent events) for all outcomes (Supplementary Fig. S1). As such, only the first hospitalisation event was included in the analysis. For all events except CVT, the event dependent exposures observed had a significant effect on the model (Table 3). There was a decrease in the number of events immediately before vaccination, indicating the presence of event dependent exposures (Supplementary Fig. S2a–d). The event dependent exposures observed for these events were not fully compensated for by implementing a pre-exposure period (2–42 days) (Supplementary Fig. S3a–d). We therefore implemented an extension to the standard SCCS model previously described [
      • Farrington C.P.
      • Whitaker H.J.
      • Hocine M.N.
      Case series analysis for censored, perturbed, or curtailed post-event exposures.
      ,
      • Farrington P.
      • Whitaker H.
      • Weldeselassie Y.G.
      Self-controlled Case Series Studies:A Modelling Guide With R.
      ], for VTE, arterial thrombosis, and splanchnic thrombosis. We also observed a significant association between the number of deaths and the occurrence of VTE (Supplementary Fig. S4) and implemented an adaption to the event dependent exposure model that accounts for high-event related mortality [
      • Ghebremichael-Weldeselassie Y.
      • Jabagi M.J.
      • Botton J.
      • et al.
      A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
      ]. The final SCCS model used for each event of interest is presented in Table 3.

      4. Discussion

      This nationwide SCCS study did not find evidence of a significantly increased risk of arterial thrombosis, CVT, splanchnic thrombosis, or VTE in the 21 days following the first, second, or booster dose of the BNT162b2 vaccine during the first year of COVID-19 vaccinations in New Zealand (19 February 2021 through 19 February 2022). We also observed no increased risk of developing a thrombotic event following vaccination across different ethnic groups in the country, including Māori (indigenous New Zealanders) and Pacific peoples. We observed a large reduction in events prior to and following vaccination, highlighting the presence of the healthy vaccine effect in our study [
      • Remschmidt C.
      • Wichmann O.
      • Harder T.
      Frequency and impact of confounding by indication and healthy vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review.
      ].
      These findings are consistent with other population based post-market studies that observed no increased risk of developing thromboembolic events following receipt of the BNT162b2 vaccine [
      • Simpson C.R.
      • Shi T.
      • Vasileiou E.
      • et al.
      First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
      ,
      • Abbattista M.
      • Martinelli I.
      • Peyvandi F.
      Comparison of adverse drug reactions among four COVID-19 vaccines in Europe using the EudraVigilance database: thrombosis at unusual sites.
      ,
      • Hviid A.
      • Hansen J.V.
      • Thiesson E.M.
      • Wohlfahrt J.
      Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: a retrospective cohort study.
      ,
      • Barda N.
      • Dagan N.
      • Ben-Shlomo Y.
      • et al.
      Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.
      ,
      • Klein N.P.
      • Lewis N.
      • Goddard K.
      • et al.
      Surveillance for adverse events after COVID-19 mRNA vaccination.
      ,
      • Houghton D.E.
      • Wysokinski W.
      • Casanegra A.I.
      • et al.
      Risk of venous thromboembolism after COVID-19 vaccination.
      ]. Conversely, a SCCS study based in the United Kingdom (UK) by Hippisley-Cox, et al found an increased risk of CVT and arterial thrombosis 15–21 days after a first dose of the BNT162b2 vaccine [
      • Hippisley-Cox J.
      • Patone M.
      • Mei X.W.
      • et al.
      Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.
      ]. However, the IRR for arterial thrombosis was low (1.06) and confidence intervals near 1.00 (1.01 to 1.10). Additionally, the confidence intervals for CVT were wide (1.39 to 9.29) due to the small number of events (6 events) observed in the study, limiting the conclusions that can be made from that study. Furthermore, only vaccinated participants (first dose only) were included and the study used a pre-risk period of 28 days to compensate for event-dependent exposures observed. Our findings suggest that due to the often-serious nature of these thrombotic events, the delay in vaccination can be prolonged and high-event mortality is sometimes observed. This can introduce bias and we implemented a modified SCCS method that was proposed specifically for COVID-19 vaccine safety studies, to account for both delays in vaccination and high-event related mortalities [
      • Ghebremichael-Weldeselassie Y.
      • Jabagi M.J.
      • Botton J.
      • et al.
      A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
      ].
      New Zealand provides a unique setting and population to study the safety of the BNT162b2 vaccine. Firstly, the country had limited to no COVID-19 cases for the first two years of the pandemic due to the government's effective execution of an elimination strategy [
      • Baker M.G.
      • Wilson N.
      • Anglemyer A.
      Successful elimination of Covid-19 transmission in New Zealand.
      ]. This coincides with our study period and allowed us to have confidence in the pharmacovigilance of the BNT162b2 vaccine since there were minimal cases of COVID-19 in the community. Therefore, it is unlikely that any adverse events observed following immunisation were a result of infection. Secondly, New Zealand has had high vaccination coverage and at the time of this study, approximately 95.5 % of the eligible population had received at least one dose of the BNT162b2 vaccine. Thirdly, we used a large and complete dataset which included information on all public and some private hospital discharges, which was linked to data on all participants who received a first, second, or booster dose of the BNT162b2 vaccine in New Zealand. Notably, during the study period, the adult formulation of the BNT162b2 vaccine was made freely available to all individuals in New Zealand aged 12 years and over as a primary vaccination course, and for individuals aged 18 years or older as a primary course and as a booster, regardless of whether they were eligible for publicly funded health and disability services.
      The use of the SCCS method also has its advantages compared to a standard cohort or case-controlled methods in that it involves within-person comparisons which allows for controlling fixed characteristics such as sex, ethnicity, and underlying health conditions. We also adjusted for seasonality to account for any variation for the risk of thrombosis at different times of the year [
      • Salehi G.
      • Sarraf P.
      • Fatehi F.
      Cerebral venous sinus thrombosis may follow a seasonal pattern.
      ,
      • Gallerani M.
      • Boari B.
      • De Toma D.
      • et al.
      Seasonal variation in the occurrence of deep vein thrombosis.
      ,
      • Lindqvist P.
      • Epstein E.
      • Olsson H.
      Does an active sun exposure habit lower the risk of venous thrombotic events? AD-lightful hypothesis.
      ]. We carried out robust sensitivity analyses to assess the assumptions of the SCCS method and accounted for both thrombotic event-dependent exposures and high-event mortality observed in our models. We included unvaccinated individuals as these cases can provide information on the timing of events, as the absence of vaccination may indicate cancellation of vaccination. Failure to consider the magnitude of the healthy vaccine effect or the association between the occurrence of an event and death would have led to bias in the estimation of the baseline risk, and a subsequent increased risk of thrombotic events after vaccination compared to this baseline period. Finally, an important strength of our study was the ability to understand the safety of the BNT162b2 vaccine in all population subgroups in New Zealand. Our finding of no increased risk across different ethnic groups including Māori and Pacific peoples, can provide reassurance to the public and policy makers on the safety of the vaccine, especially as these groups were not represented in the BNT162b2 vaccine phase III clinical trials [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ].
      Our study is subject to several limitations. Firstly, we relied on hospital diagnosis codes to define our outcome measures and assessment of clinical records was not conducted to validate the diagnoses or codes used. Secondly, we were limited in the length of our study period. Although we followed individuals for a full year, extremely rare conditions such as CVT are difficult to detect, especially in New Zealand which has a relatively small population size (approximately 5.1 million people) [
      • StatsNZ
      Taturanga Aotearoa. Population.
      ]. Furthermore, the effects of any seasonal variation in the model may not have been fully adjusted for as this was based on a one-year cycle. Thirdly, our study used hospital discharge information only, including coded clinical data for inpatients and outpatients. Although many of the thrombotic events evaluated in this study can be serious and involve hospitalisation, some events, for example deep vein thrombosis (DVT), are typically treated in the primary care setting. As such, diagnoses made in primary care are not be included in our analyses and the incidence rates for certain events could be underestimated.

      5. Conclusion

      There was no observed association between the BNT162b2 vaccine and arterial thrombosis, CVT, splanchnic thrombosis, and VTE, requiring hospitalisation, during the 21 days following immunisation in the general population or in different ethnic groups in New Zealand. Therefore, this study provides reassurances on thrombotic safety of the BNT162b2 vaccine in both an international and New Zealand specific context. Further studies, with substantial population sizes are needed to assess the risk of CVT, which is an extremely rare event.

      Data availability

      The data that support the findings of this study are not able to be made publicly available due to privacy and ethical restrictions outlined by New Zealand Legislation.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We gratefully acknowledge the assistance of the National Immunisation Programme within Health New Zealand (Te Whatu Ora), the Ministry of Health New Zealand (Manatū Hauora) and Medsafe with this study. The research was supported and critically reviewed by Janelle Duncan and Dr Christian Marchello of the National Immunisation Programme and Dr Susan Kenyon of the Clinical Risk Management branch within Medsafe. Equity consultation and review was provided by the Equity group within the National Immunisation Programme. Dr Laura Young and members of the COVID-19 Vaccine Independent Safety Monitoring Board provided expert advice. Open access funding was provided by the National Immunisation Programme 2022/23 Budget from the Ministry of Health, New Zealand.

      Funding

      The work reported in this publication was undertaken by the Vaccine Safety Surveillance and Research Group during the COVID-19 Vaccine and Immunisation programme within the Ministry of Health New Zealand. Funding for this programme was provided by the New Zealand government. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Appendix A. Supplementary data

      References

        • Ho F.K.
        • Man K.K.
        • Toshner M.
        • et al.
        Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort.
        Mayo Clin. Proc. 2021; 96: 2587-2597https://doi.org/10.1016/j.mayocp.2021.07.002
        • Malas M.B.
        • Naazie I.N.
        • Elsayed N.
        • et al.
        Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis.
        EClinicalMedicine. 2020; 29100639https://doi.org/10.1016/j.eclinm.2020.100639
        • Moschonas I.C.
        • Tselepis A.D.
        SARS-CoV-2 infection and thrombotic complications: a narrative review.
        J. Thromb. Thrombolysis. 2021; 52: 111-123https://doi.org/10.1007/s11239-020-02374-3
        • Andrews N.J.
        • Stowe J.
        • Ramsay M.E.
        • Miller E.
        Risk of venous thrombotic events and thrombocytopenia in sequential time periods after ChAdOx1 and BNT162b2 COVID-19 vaccines: a national cohort study in England.
        Lancet Reg. Health Eur. 2022; 13100260https://doi.org/10.1016/j.lanepe.2021.100260
        • Simpson C.R.
        • Shi T.
        • Vasileiou E.
        • et al.
        First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
        Nat. Med. 2021; 27: 1290-1297https://doi.org/10.1038/s41591-021-01408-4
        • Hippisley-Cox J.
        • Patone M.
        • Mei X.W.
        • et al.
        Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.
        BMJ. 2021; 374n1931https://doi.org/10.1136/bmj.n1931
        • Medsafe
        New Zealand Data Sheet. Vaxzevria. Version 040422.
        (Available from:) (Accessed Feburary 24 2022])
        • European Medicines Agency
        Jcvden (previously COVID-19 vaccine Janssen) : EPAR- Product Information.
        (Available from:) ([Accessed June 17 2022])
        • Ministry of Health New Zealand
        COVID-19: Vaccines.
        (Available from:) (Accessed January 24 2022])
        • Polack F.P.
        • Thomas S.J.
        • Kitchin N.
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
        N. Engl. J. Med. 2020; 383: 2603-2615https://doi.org/10.1056/NEJMoa2034577
        • Abbattista M.
        • Martinelli I.
        • Peyvandi F.
        Comparison of adverse drug reactions among four COVID-19 vaccines in Europe using the EudraVigilance database: thrombosis at unusual sites.
        J. Thromb. Haemost. 2021; 19: 2554-2558https://doi.org/10.1111/jth.15493
        • Hviid A.
        • Hansen J.V.
        • Thiesson E.M.
        • Wohlfahrt J.
        Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: a retrospective cohort study.
        Ann. Intern. Med. 2022; 175: 541-546https://doi.org/10.7326/M21-2452
        • Barda N.
        • Dagan N.
        • Ben-Shlomo Y.
        • et al.
        Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.
        N. Engl. J. Med. 2021; 385: 1078-1090https://doi.org/10.1056/NEJMoa2110475
        • Klein N.P.
        • Lewis N.
        • Goddard K.
        • et al.
        Surveillance for adverse events after COVID-19 mRNA vaccination.
        JAMA. 2021; 326: 1390-1399https://doi.org/10.1001/jama.2021.15072
        • Houghton D.E.
        • Wysokinski W.
        • Casanegra A.I.
        • et al.
        Risk of venous thromboembolism after COVID-19 vaccination.
        J. Thromb. Haemost. 2022; 20: 1638-1644https://doi.org/10.1111/jth.15725
        • Medsafe
        COVID-19. Safety Monitoring. Overview of Vaccine Reports. Safety Report #43- 30 April 2022.
        (Available from:) (Acessed 6 June 2022.])
        • Alhashim A.
        • Hadhiah K.
        Extensive cerebral venous sinus thrombosis (CVST) after the first dose of Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine without thrombotic thrombocytopenia syndrome (TTS) in a healthy woman.
        Am. J. Case Reports. 2022; 23: e934741-e934744https://doi.org/10.12659/AJCR.934744
        • Tobaiqy M.
        • MacLure K.
        • Elkout H.
        • Stewart D.
        Thrombotic adverse events reported for moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines: comparison of occurrence and clinical outcomes in the EudraVigilance database.
        Vaccines. 2021; 9: 1326https://doi.org/10.3390/vaccines9111326
        • Prickett K.C.
        • Habibi H.
        • Carr P.A.
        COVID-19 vaccine hesitancy and acceptance in a cohort of diverse new zealanders.
        Lancet Reg. Health West Pac. 2021; 14100241https://doi.org/10.1016/j.lanwpc.2021.100241
        • StatsNZ
        Taturanga Aotearoa. New Zealand's population reflects growing diversity.
        (Available from:) ([Accessed 5 April 2022])
        • Steyn N.
        • Binny R.N.
        • Hannah K.
        • et al.
        Māori and Pacific People in New Zealand Have Higher Risk of Hospitalisation for COVID-19.
        medRxiv, 2021https://doi.org/10.1101/2020.12.25.20248427 (p. 2020.12. 25.20248427)
        • Steyn N.
        • Binny R.N.
        • Hannah K.
        • et al.
        Estimated inequities in COVID-19 infection fatality rates by ethnicity for aotearoa New Zealand.
        N. Z. Med. J. 2020; 133: 28-39https://doi.org/10.1101/2020.04.20.20073437
        • Graham R.
        • Masters-Awatere B.
        Experiences of Māori of aotearoa New Zealand's public health system: a systematic review of two decades of published qualitative research.
        Aust. N. Z. J. Public Health. 2020; 44: 193-200https://doi.org/10.1111/1753-6405.12971
        • Whitehead J.
        • Scott N.
        • Atatoa-Carr P.
        • Lawrenson R.
        Will access to COVID-19 vaccine in aotearoa be equitable for priority populations?.
        N. Z. Med. J. 2021; 134: 25-34https://doi.org/10.1093/ije/dyab168.708
        • Marriott L.
        • Sim D.
        Indicators of inequality for Maori and Pacific people.
        J. N. Z. Stud. 2015; 20 (10.3316): 24-50
        • O’Hallahan J.
        • McNicholas A.
        • Galloway Y.
        • et al.
        Delivering a safe and effective strain-specific vaccine to control an epidemic of group B meningococcal disease.
        N. Z. Med. J. 2009; : 122
        • Paterson J.
        • Schluter P.
        • Percival T.
        • Carter S.
        Immunisation of a cohort Pacific children living in New Zealand over the first 2 years of life.
        Vaccine. 2006; 24: 4883-4889https://doi.org/10.1016/j.vaccine.2006.02.050
        • Pointon L.
        • Howe A.S.
        • Hobbs M.
        • et al.
        Evidence of suboptimal maternal vaccination coverage in pregnant New Zealand women and increasing inequity over time: a nationwide retrospective cohort study.
        Vaccine. 2022; 40: 2150-2160https://doi.org/10.1016/j.vaccine.2022.02.079
        • Baker M.G.
        • Wilson N.
        • Anglemyer A.
        Successful elimination of Covid-19 transmission in New Zealand.
        N. Engl. J. Med. 2020; 383e56https://doi.org/10.1056/NEJMc2025203
        • Ministry of Health New Zealand
        COVID-19 Cases: Current Cases.
        (Available from:) ([Accessed June 17 2022])
        • Whitaker H.J.
        • Farrington C.P.
        • Spiessens B.
        • Musonda P.
        Tutorial in biostatistics: the self-controlled case series method.
        Stat. Med. 2006; 25: 1768-1797https://doi.org/10.1002/sim.2302
        • Farrington C.
        Relative incidence estimation from case series for vaccine safety evaluation.
        Biometrics. 1995; 51: 228-235https://doi.org/10.2307/2533328
        • Ghebremichael-Weldeselassie Y.
        • Jabagi M.J.
        • Botton J.
        • et al.
        A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.
        Stat. Med. 2022; https://doi.org/10.1002/sim.9325
        • Brighton Collaboration
        Safety Platform for Emergency VACcines (SPEAC). Priority List of Adverse Events of Special Interest: COVID-19. V2.0.
        (Available from:) (Accessed 10 February 2022])
        • Ministry of Health New Zealand
        Health Statistics. National Minimum Dataset (hospital events).
        (Available from:) (Accessed March, 2 2022])
        • Ministry of Health New Zealand
        NZ Health System. Guide to eligibility for publicly funded health services.
        (Available from:) ([Accessed March, 2 2022])
        • Ministry of Health New Zealand
        COVID-19 Vaccines- Your Privacy- COVID Immunisation Register (CIR) privacy statement.
        (Available from:) (Acessed 6 June 2022.])
        • COVID-19 GOVT NZ
        Time between doses of COVID-19 Vaccine extended- media release 12 Aug 2021.
        (Available from:) (Acessed 6 June 2022.])
        • COVID-19 GOVT NZ
        Get your second dose.
        (Available from:) ([Accessed 11 March 2022])
        • COVID-19 GOVT NZ
        Latest news- Booster vaccine available from end of November – statement released 15 Nov 2021.
        (Available from:) (Accessed [February 16, 2022])
        • Farrington C.
        • Whitaker H.
        Semiparametric analysis of case series data.
        J. R. Stat. Soc.: Ser. C: Appl. Stat. 2006; 55: 553-594https://doi.org/10.1111/j.1467-9876.2006.00554.x
        • Salehi G.
        • Sarraf P.
        • Fatehi F.
        Cerebral venous sinus thrombosis may follow a seasonal pattern.
        J. Stroke Cerebrovasc. Dis. 2016; 25: 2838-2843https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.07.045
        • Gallerani M.
        • Boari B.
        • De Toma D.
        • et al.
        Seasonal variation in the occurrence of deep vein thrombosis.
        Medical Science Monitor. 2004; 10: CR191-CR196
        • Lindqvist P.
        • Epstein E.
        • Olsson H.
        Does an active sun exposure habit lower the risk of venous thrombotic events? AD-lightful hypothesis.
        J. Thromb. Haemost. 2009; 7: 605-610https://doi.org/10.1111/j.1538-7836.2009.03312.x
        • Farrington C.P.
        • Whitaker H.J.
        • Hocine M.N.
        Case series analysis for censored, perturbed, or curtailed post-event exposures.
        Biostatistics. 2009; 10: 3-16https://doi.org/10.1093/biostatistics/kxn013
        • Farrington P.
        • Whitaker H.
        • Weldeselassie Y.G.
        Self-controlled Case Series Studies:A Modelling Guide With R.
        2018https://doi.org/10.1201/9780429491313
        • Remschmidt C.
        • Wichmann O.
        • Harder T.
        Frequency and impact of confounding by indication and healthy vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review.
        BMC Infect. Dis. 2015; 15: 1-15https://doi.org/10.1186/s12879-015-1154-y
        • StatsNZ
        Taturanga Aotearoa. Population.
        (Available from:) ([Accessed 5 April 2022])