Largest Covid vaccine study links it to higher risk of neurological, blood and heart disorders

Largest Covid vaccine study links it to higher risk of neurological, blood and heart disorders

An international coalition looked at 13 medical conditions among 99 million vaccine recipients in 8 countries to identify higher rates of those conditions after receiving the shots.

They confirmed that the shots made by Pfizer, Moderna, and AstraZeneca are linked to significantly higher risk of five medical conditions – including a nerve-wasting condition that leaves people struggling to walk or think.

The study also warned of several other disorders that warrant further investigation, including a brain swelling disorder and Moderna’s spikevax.

3.1. Neurological conditions

There was a statistically significant increase in GBS cases within 42 days after a first ChAdOx1 dose (OE ratio = 2.49; 95 % CI: 2.15, 2.87), indicating a prioritised safety signal (Table 3). Seventy-six GBS events were expected, and 190 events were observed (Fig. 1). The OE ratio for ADEM within 42 days after a first mRNA-1273 dose also fulfilled the significance threshold of a prioritised safety signal (3.78; 95 % CI: 1.52, 7.78), with two expected events compared with seven observed events (Fig. 1).

Statistically significant differences were also found for transverse myelitis (OE ratio = 1.91; 95 % CI: 1.22, 2.84) and ADEM (OE ratio = 2.23; 95 % CI: 1.15, 3.90) after a first ChAdOx1 dose. Bell’s palsy had an increased OE ratio after a first dose of BNT162b2 (1.05; 95 % CI: 1.00, 1.11) and mRNA-1273 (1.25; 95 % CI: 1.11, 1.39). There were also increased OE ratios for febrile seizures following a first and second dose of mRNA-1273 (1.36, 95 % CI: 1.02, 1.77 and 1.44, 95 % CI: 1.04, 1.95, respectively), and for generalised seizures following a first mRNA-1273 dose (1.15, 95 % CI: 1.10, 1.20) and a fourth BNT162b2 dose (1.09, 95 % CI: 1.04, 1.14). No increased OE ratios were identified following a third dose of any vaccine. The results are concordant with the OE ratios of homologous schedules; however, an increased OE ratio for generalized seizures following a homologous schedule of four doses of mRNA-1273 (1.33; 95 % CI: 1.07, 1.63) was identified (Fig. 1). These outcomes did not meet the threshold for a prioritised safety signal following vaccination.

3.2. Hematologic conditions

The OE ratio of CVST was 3.23 (95 % CI: 2.51–4.09) within 42 days after a first dose of ChAdOx1, fulfilling the threshold of a prioritised safety signal (Table 4). In total, 21 events were expected, while 69 events were observed (Fig. 2).

Increased OE ratios were also identified for thrombocytopenia after a first dose of ChAdOx1 (1.07; 95 % CI: 1.03, 1.12), BNT162b2 (1.11; 95 % CI: 1.08, 1.14), and mRNA-1273 (1.33; 95 % CI 1.25, 1.42), as well as after a third dose of ChAdOx1 (1.95; 95 % CI: 1.29, 2.84). Immune thrombocytopenia also demonstrated increased OE ratios after a first dose of ChAdOx1 (1.40; 95 % CI: 1.24, 1.58) and BNT162b2 (1.08; 95 % CI: 1.01, 1.16). Pulmonary embolism OE ratios were increased following first doses of ChAdOx1 (1.20; 95 % CI: 1.16, 1.24), BNT162b2 (1.29; 95 % CI: 1.26, 1.32), and mRNA-1273 (1.33, 95 % CI: 1.26, 1.40), as well as after a third dose of ChAdOx1 (1.88; 95 % CI: 1.32, 2.58). The OE ratio of CVST was 1.49 (95 % CI: 1.26, 1.75) after a first dose and 1.25 (95 % CI: 1.06, 1.46) after a second dose of BNT162b2. An increased OE ratio for SVT was found after a first dose of BNT162b2 (1.25; 95 % CI: 1.17, 1.34) and mRNA-1273 (1.23; 95 % CI: 1.03, 1.47); a second dose of mRNA-1273 (1.17; 95 % CI: 1.01, 1.36); and a fourth dose of BNT162b2 (1.30, 95 % CI: 1.06, 1.59) and mRNA-1273 (1.53, 95 % CI: 1.05, 2.16). These outcomes did not meet the threshold for a prioritised safety signal following vaccination.

3.3. Cardiovascular conditions

Increased OE ratios fulfilling the threshold of prioritised safety signals for myocarditis were consistently identified following a first, second and third dose of mRNA vaccines (BNT162b2 and mRNA-1273) (Table 4). The highest OE ratio was observed following a first and second dose of mRNA-1273 (3.48; 95 % CI: 3.00, 4.01 and 6.10; 95 % CI: 5.52, 6.72, respectively). The OE ratio following a third dose of mRNA-1273 was 2.01 (95 % CI: 1.60, 2.49). The numbers of events for up to four doses of homologous schedules are shown in Fig. 3. The OE ratios of homologous schedules align with the aggregated OE ratios. The homologous OE for myocarditis following four doses of mRNA-1273 vaccine could not be estimated due to a lack of observed events.

Similarly, the OE ratio for pericarditis fulfilled the threshold of a prioritised safety signal following a first and fourth dose of mRNA-1273, with OE ratios of 1.74 (95 % CI: 1.54, 1.97) and 2.64 (95 % CI: 2.05, 3.35) respectively. An increased ratio of 6.91 (95 % CI: 3.45, 12.36), fulfilling the threshold of a prioritised safety signal, was also observed following a third dose of ChAdOx1. The aggregated OE ratios for pericarditis were increased following all doses of all the three vaccines presented (Table 4). The results are very similar to the ratios of homologous schedules (Fig. 3), except for the OE ratio of 1.23 (95 % CI: 0.45–2.69) after receipt of the fourth mRNA-1273 dose, which did not meet the threshold for a safety signal. The homologous OE ratio following a third dose of ChAdOx1 was not reported as only a small number of third doses of ChAdOx1 were given across study sites (Table1).

the study

Since declaration of the COVID-19 pandemic by the World Health Organization (WHO) on March 11, 2020 [1] more than 13.5 billion doses of COVID-19 vaccines have been administered worldwide [2]. As of November 2023, at least 70.5 % of the world’s population had received at least one dose of a COVID-19 vaccine [2]. This unparalleled scenario underscores the pressing need for comprehensive vaccine safety monitoring as very rare adverse events associated with COVID-19 vaccines may only come to light after administration to millions of individuals.

In anticipation of this unprecedented global rollout of COVID-19 vaccines, the Safety Platform for Emergency vACcines (SPEAC) initiative formulated a list of potential COVID-19 vaccine adverse events of special interest (AESI) in 2020 [3]. AESI selection was based on their pre-established associations with immunization, specific vaccine platforms or adjuvants, or viral replication during wild-type disease; theoretical concerns related to immunopathogenesis; or supporting evidence from animal models using candidate vaccine platforms [3].

Observed versus (vs.) expected (OE) analysis was integral in identifying thrombosis with thrombocytopenia syndrome (TTS) as a safety signal, prompting the suspension of use of the ChAdOx1 (AstraZeneca COVID-19 vaccine) on March 11, 2021, in Denmark and Norway [7], [8].

These evaluations are not only valuable early-on in large-scale vaccine deployment, but also as the vaccination program matures, especially if they can be conducted in a multi-country context. We conducted a global cohort study following the Observed vs. Expected Analyses of COVID-19 Adverse Events of Special Interest Study Protocol [9] with data from 10 sites across eight countries participating in the unique Global COVID Vaccine Safety (GCoVS) Project [10] of the Global Vaccine Data Network™ (GVDN®) [11]. The GCoVS Project, initiated in 2021, is a Centers for Disease Control and Prevention (CDC) funded global collaboration of investigators and data sources from multiple nations for the purpose of COVID-19 vaccine safety monitoring.

The study periods varied across countries, commencing on the date of the site-specific COVID-19 vaccination program rollout, and concluding at the end of data availability (Table 1). In general, the study periods spanned from December 2020 until August 2023. The shortest study period observed occurred in Australia – New South Wales, including 11 months from February 2021 to December 2021. Argentina had the longest study period, from December 2020 to August 2023, encompassing a total of 32 months.

2.4.2. COVID-19 vaccines

As of November 2023, multiple vaccines against COVID-19 were in use by the GCoVS sites representing multiple platform types such as inactivated, nucleic acid-based (mRNA), protein-based, and non-replicating viral vector platforms (Table 2). For this manuscript, we focused on three vaccines that recorded the highest number of doses administered, Pfizer/BioNTech BNT162b2, Moderna mRNA-1273, and Oxford/Astra Zeneca/Serum Institute of India ChAdOx1 vaccines. The cumulative number of doses of other vaccines administered (n) across study sites were relatively low, with exceptions for the inactivated Sinopharm (n = 134,550) and Sinovac (n = 31,598) vaccines, the protein-based Novavax (n = 66,856) vaccine, and the adenovirus-vector Janssen/Johnson & Johnson (n = 1,137,505) and Gamaleya Research Institute/Sputnik (n = 84,460) vaccines. The total number of doses of each vaccine brand administered are outlined in Table 2. Exposure to COVID-19 vaccine by platform/type, brand, and dose data were available at the individual level to determine the number of observed cases by vaccine type/brand and dose profile and within the 0–42 days post-vaccination risk interval.

Table 2. Total number of vaccinations by brand.