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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration (2024)

Chapter: 4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines

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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines This chapter describes the potential relationship between COVID-19 vaccines and sudden sensorineural hearing loss (SSNHL) and tinnitus (see Boxes 4-1 and 4-2 for all conclusions in this chapter). SENSORINEURAL HEARING LOSS BOX 4-1 Conclusions for Sensorineural Hearing Loss Conclusion 4-1: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and sensorineural hearing loss. Conclusion 4-2: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and sensorineural hearing loss. Conclusion 4-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and sensorineural hearing loss. Conclusion 4-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and sensorineural hearing loss. Background The whole auditory system is how humans’ access and make sense of environmental sounds. It is a multistage system characterized by encoding of environmental auditory stimuli by peripheral structures and decoding of the stimuli by central structures in the brainstem and cerebral cortex (Pickles, 2013). Peripherally, auditory energy is funneled into the pinna toward the tympanic membrane (eardrum), where it is converted to mechanical energy and moves along the ossicles in the middle ear to the cochlea, which contains the organ of Corti, which acts to encode auditory signals as neuroelectric signals (e.g., action potentials) that are transmitted to the temporal lobe via the eighth nerve and brainstem for decoding and processing (Pickles, 2013). Damage can occur at any step in this process, resulting in different types of hearing loss. Conductive hearing loss is characterized by an inability for the outer and middle ear to transmit signals to the inner ear (e.g., rupture in the tympanic membrane, fluid in the middle ear) and is PREPUBLICATION COPY—Uncorrected Proofs

114 VACCINE EVIDENCE REVIEW often transient (e.g., fluid drains from the ear) or can be addressed via medical or surgical interventions (Lee, 2013; Pickles, 2013). Sensorineural hearing loss is distinguished by disruption in encoding auditory information in the cochlea or along the eighth nerve and is usually permanent. Central hearing loss or auditory processing disorders (Martin and Jerger, 2005; Task Force on Central Auditory Processing Consensus Development, 1996), although more poorly understood and considered rare, especially among adults, occur when sound is encoded normally in the peripheral ear (e.g., no sign of sensorineural or conductive loss but deficits in the neural processing of auditory information mean that individuals struggle with understanding it despite functioning peripheral hearing (Katz, 2015). Audiologists and otolaryngologists diagnose hearing loss using a comprehensive assessment battery, including various measures assessing different processes of the auditory system (Katz, 2015). The criterion standard for peripheral hearing is pure-tone audiometry, which identifies the softest volume at which tones at different frequencies can be detected. A combination of methods of presenting the tone via air conduction (e.g., traditional headphones that stimulate the entire outer, middle, and inner ears) and bone conduction (e.g., oscillator that directly stimulates the cochlea) distinguish different types of hearing loss (Katz, 2015). Self-reported hearing has relatively poor agreement with the criterion standard, with sensitivity and specificity reported as 41–65 percent and 81–88 percent among U.S. adults over 20 years old, respectively (Agrawal et al., 2008). Moreover, accuracy and the direction of misclassification (e.g., directional difference between self-report and criterion measured degree of hearing loss) differs by key demographic variables, including age, race, and sex; older White men are more likely to underestimate their level of hearing loss relative to younger Black women (Kamil et al., 2015). The relatively poor accuracy of self-reported hearing can be attributed to the insidious onset of age-related hearing loss masking the change, perceived normalcy for a given age group, stigma, or projection (believing that others are mumbling or speaking poorly). Moreover, understanding speech requires both an auditory (e.g., accessing sound) and cognitive (e.g., making sense of the information) component, and listening with hearing loss can contribute to fatigue from cognitive load placed on the brain when decoding poor peripheral signals (Hornsby et al., 2016; Wingfield et al., 2005). Some may misattribute hearing loss to cognitive processes and vice versa when considering their own hearing levels. Although the procedures are standardized, the actual clinical cut points vary by professional organizations and are at the discretion of the provider. Population estimates vary by the definition and whether hearing loss estimates are limited to bilateral or unilateral (estimates increase when including unilateral loss) (Lin et al., 2011). Using the commonly cited World Health Organization (WHO) cutoffs from before 2021, estimates suggest that 23 percent of U.S. individuals over age 12 have bilateral hearing loss and that prevalence increases with age, from less than 1 percent at 20–29 years to more than 80 percent over 80 years (Goman and Lin, 2016). WHO suggests approximately 20 percent of the global population has hearing loss (WHO). Among the types of hearing loss, specific reliable national estimates are not reported. Permanent conductive hearing loss is relatively rare (Cruickshanks et al., 1998), and sensorineural hearing loss is the overwhelmingly most common permanent form, with the majority of cases being attributed to age (Reed et al., 2023; Yamasoba et al., 2013). However, estimates vary by definition of hearing loss and global region and are limited due to the often-transient nature of conductive hearing loss, relatively low uptake of hearing assessment within health systems, and lack of feasibility for comprehensive hearing assessment in epidemiological studies (Chadha et al., 2021; Katz, 2015; Powell et al., 2021). PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 115 Known individual risk factors for sensorineural hearing loss include congenital and progressive genetic conditions, excessive noise, certain medications and chemicals, health behaviors (e.g., smoking), chronic cardiovascular conditions, viral infections, and age-related cellular degeneration (Agrawal et al., 2008; Eggermont, 2017; Van Eyken et al., 2007). The majority of adult hearing loss is often labeled as “age-related” and attributed to a combination of exposures that insidiously degrades hearing acuity such that changes are so subtle they often go unnoticed until they are more pronounced (Lin et al., 2011; Yamasoba et al., 2013). SSNHL is characterized as an acute change (e.g., within a 72-hour period). The specific mechanisms are poorly characterized as several risk factors and potential causes have been reported including infection, trauma, autoimmune disease, certain medications (e.g., aminoglycosides), and certain disorders of the inner ear (e.g., Meniere’s) (Kuhn et al., 2011; Schreiber et al., 2010; Stachler et al., 2012). It is relatively rare (approximately 5–20 of 100,000 people yearly), but estimates are mostly reliant on high-income countries (Stachler et al., 2012). Estimates suggest that approximately 40–60 percent of cases will recover to normal levels in a few weeks of follow-up (Kuhn et al., 2011; Mattox and Simmons, 1977; Wilson et al., 1980). However, the incidence and recovery rate are not well documented in low- and middle-income countries. Moreover, there is variation in the literature of the different definitions for risk- windows and specific change in audiometric thresholds. Mechanisms The mechanistic evidence for a biologically plausible association between hearing loss and COVID-19 vaccination is limited; a paucity of work offers direct evidence. Similarly, there is little mechanistic evidence whether COVID-19 infection causes hearing loss. Much of the relevant literature is theoretical or postulated based on adjacent research. Moreover, no literature offers substantive discussion of the potential for increased risk of an association by comorbid conditions, genetic predisposition, concurrent pharmacologic agent, or environmental exposures. The initial consideration is the possible direct viral involvement of the inner ear or the vestibulocochlear nerve (Kaliyappan et al., 2022). The inflammatory response, possibly cochleitis or neuritis, could be an effect of the immune activation by the vaccine. The hyperproduction of proinflammatory cytokines in response to the vaccine could inadvertently affect the audio vestibular system, leading to symptoms such as vertigo, tinnitus, and hearing loss. Such a hyperinflammatory state is known to cause tissue damage and could be particularly detrimental to the sensitive structures of the ear (Kamogashira et al., 2022). Specifically, the response to BNT162b2 1 provides a hypothetical framework. Studies demonstrate that this vaccine elicits a strong immune response, characterized by high levels of neutralizing antibodies and robust T cell responses, including antigen-specific CD8+ and Th1-type CD4+ T cells (Sadarangani et al., 2021). Although this is crucial for protective immunity, it also raises the potential for unintended auditory effects. The inflammatory environment can indirectly inflict damage on the intricate anatomy of the ear, affecting or occluding small areas within it. The vigorous immune response, especially the aspects involving cell-mediated immunity and cytokine production, could inadvertently affect the ear through either direct inflammatory damage or secondary effects, such as vascular complications. 1 The COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. PREPUBLICATION COPY: Uncorrected Proofs

116 VACCINE EVIDENCE REVIEW Others have postulated about molecular mimicry and immunological considerations, such as an autoimmune-like response, where antibodies or T cells, activated by the vaccine, might erroneously recognize inner ear antigens as viral epitopes and trigger an immune attack (Ahmed et al., 2022). Given the specificity and sensitivity of the immune response, particularly the adaptive immunity involving antigen-specific T cell and B cell responses, this cross-reactivity could be a plausible mechanism for vaccine-induced auditory damage. Last, the unique anatomical and physiological characteristics of the cochlea and semicircular canals, notably their isolated blood supply, make them particularly vulnerable to ischemic events (Tabuchi et al., 2010). Vaccine-induced alterations in the cardiovascular system, either directly or through an immune-mediated pathway, could lead to thrombosis or hypoxia in these areas, resulting in auditory dysfunction. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding sensorineural hearing loss and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 4-1 presents five studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 117 TABLE 4-1 Epidemiological Studies in the Sensorineural Hearing Loss Evidence Review Study Design and Control Age Number of Author Group Location Data Source Vaccine(S) Range N Events Results (95% CI) BNT162b2 305 All vaccines: IR 0.6 (probable; Formeister 185.4 minimum estimate) Surveillance; mRNA-1273 15–93 222 et al. USA VAERS million and 28.0 (maximum single arm years (2022) doses estimate) cases of Ad26.COV2.S SSNHL per 100,000 28 people per year 167.0 3.20 per 1 million BNT162b2 million doses doses Frontera et Surveillance; 128.1 Not 3.08 per 1 million USA VAERS mRNA-1273 al. (2022) single arm ≥12 million doses reported doses years 11.6 6.29 per 1 million Ad26.COV2.S million doses doses 244 vaccinees 1.7% of all Clinical Otology BNT162b2 10 vaccinated Leong et convenience NY, NY, clinic at an 16–101 individuals had al. (2023) sample; USA academic mRNA-1273 123 vaccinees 9 years adjudicated new single arm center Ad26.COV2.S 16 vaccinees 1 hearing loss Dose 1: 111 IRR 0.8 (0.6–1.0) Population Finnish BNT162b2 Dose 2: 104 IRR 0.8 (0.6–1.2) Nieminen 5.5 million based population 0 to ≥80 et al. Finland individuals (total Cohort; pre information years (2023) cohort) Dose 1: 15 IRR 0.8 (0.5–1.4) and post system mRNA-1273 Dose 2: 20 IRR 1.2 (0.7–1.9) PREPUBLICATION COPY: Uncorrected Proofs

118 VACCINE EVIDENCE REVIEW TABLE 4-1 Continued Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) Dose 1: 2.6 91 SIR 1.35 (1.09–1.65) Population million 16 to Yanir et al. based Clalit Health BNT162b2 vaccinees Israel ≥65 (2022) Cohort; pre Services Dose 2: years and post 2.4 79 SIR 1.23 (0.98–1.53) million vaccinees NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The three approved COVID-19 vaccines in the UK are BNT162b2, mRNA-1273, and ChAdOx1-S. Number of events refers to events in vaccinees only. CI: confidence interval; IQR: interquartile range; IR: incidence rate; SIR: standardized incidence rate; VAERS: Vaccine Adverse Event Reporting System. SOURCES: Formeister et al., 2022; Frontera et al., 2022; Leong et al., 2023; Nieminen et al., 2023; Yanir et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 119 Nieminen et al. (2023) compared the incidence rate of SSNHL in the 30-day window preceding vaccination and 0–54 days and more than 54 days after vaccination to that between January 1, 2019, and March 1, 2020, using a national Finnish electronic health database (n = 5.5 million people); excluding those with pre-existing recent diagnosis of SSNHL from the period immediately before the study (2015–2018). Finland’s national vaccination register provided the vaccination dates and product names. SSNHL was identified using an ICD-10 diagnostic code for specialized care visits and from hospital wards. Comorbid conditions were identified from multiple sources. Models were adjusted for calendar time, SARS-CoV-2 infection, demographic, cardiovascular, chronic comorbidities, and health care use covariates. Relative to the incidence before March 2020, adjusted models suggest no increased risk in the initial 0–54-day risk period after the first dose or second dose with BNT162b2 (Dose 1: IR 0.8, 95% CI: 0.6–1.0; Dose 2: IRR 0.8, 95% CI: 0.6–1.2), or mRNA-1273 2 (Dose 1: IR 0.8, 95% CI: 0.5–1.4; Dose 2: IRR 1.2, 95% CI: 0.7–1.9). Secondary models examining risk after 54 days postvaccination and after a third dose likewise yielded no associations. Yanir et al. (2022) used the Clalit Health Services database in Israel to estimate the incidence of SSNHL after first and second doses of BNT162b2 from December 20, 2020, to April 30, 2021. Subsequent analysis compared estimates to the incidence of SSNHL from the same database in 2018 and 2019 and developed age- and sex- standardized incidence ratios. SSNHL was identified using a broad array of ICD-9 codes for hearing loss (388.2, 389.1, 389.10–389.13, 389.15–389.18, 389.8, and 389.9) and concurrent prednisone use within 30 days of diagnosis. The authors reported that 2.6 million people (mean [SD] age, 46.8 [19.6] years; 51.5 percent female) received the first dose, with 91 cases of SSNHL reported. Of these, 2.4 million (93.8 percent) received the second dose, with 79 cases of SSNHL reported. The age- and sex-weighted standardized incidence ratios (SIR) were 1.35 (95% CI: 1.09–1.65) after the first dose and 1.23 (95% CI: 0.98–1.53) after the second dose when using 2018 data as a reference (the sensitivity analysis was similar when using 2019 data). Leong et al. (2023) leveraged a clinical convenience sample from an otology clinic (NYC, NY) (rather than prospective outreach) from May to July 2021 to characterize the incidence of hearing loss after COVID-19 vaccination. Among 500 individuals who completed screening (median age 56.6 years; 59.4 percent female), 420 reported being vaccinated (58.4 percent BNT162b2, 29.1 percent mRNA-1273, 3.3 percent Ad26.COV2.S); 21 (5 percent) reported hearing loss within 4 weeks of vaccination. However, after comprehensive audiologic and otologic evaluation, only seven cases (1.7 percent of vaccinated individuals) were deemed to be SSNHL; the rest represented new or exacerbated symptoms of known pathologies of hearing loss that did not represent SSNHL definition or were unrelated to vaccination. The study did not compare vaccinated to unvaccinated individuals. Despite concerns with selection bias, recall bias and confounding, a key finding from this paper was that self-reported declines in hearing after vaccination may be unreliable, as a majority of cases were attributable to other etiologies. Inaccurate reporting of tinnitus may lead to overestimation of observed associations. Two included studies used data from the U.S. Vaccine Adverse Events Reporting System (VAERS). For denominators, each of these studies utilized publicly available data from the CDC on the total number of individuals vaccinated with COVID-19 vaccines and the total number of doses administered in the United States during the time frames of interest. As part of a larger analysis of neurologic events after COVID-19 vaccination, Frontera et al. (2022) reported an 2 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. PREPUBLICATION COPY: Uncorrected Proofs

120 VACCINE EVIDENCE REVIEW incidence rate (IR) of 3.26 cases of hearing loss identified by free text or automated coding per 1,000,000 vaccines (IR per 1,000,000 by vaccine type: 3.20 BNT162b2, 3.08 mRNA-1273, 6.29 Ad26.COV2.S) between January 1, 2021, and June 14, 2021 (306.9 million COVID-19 vaccine doses; 314,610 total adverse events). The number of hearing loss events are not specifically reported (Frontera et al., 2022). Formeister et al. (2022) described the incidence rate of SSNHL in the initial 7-month period of the U.S. vaccination campaign (December 14, 2020, to July 16, 2021). The authors identified 2,170 reports of hearing loss after vaccination in VAERS (search terms: sudden hearing loss, deafness, deafness neurosensory, deafness unilateral, deafness bilateral, and hypoacusis). Of those, the authors deemed 555 events as credible because they occurred within 21 days of vaccination and had one of the following: reference to an audiologic assessment, evaluation by an otolaryngologist, audiologist, or other physician resulting in diagnosis of SSNHL, or evaluation by an otolaryngologist resulting in magnetic resonance imaging and/or treatment with systemic or intratympanic steroid medication. The resultant estimates of annual incidence of SSNHL after COVID-19 vaccination in VAERS data were between 0.6 (probable; minimum estimate) and 28.0 (maximum estimate) cases per 100,000 people per year. The authors note that this is lower than or similar to the estimated annual U.S. incidence (11–77 per 100,000 people per year) (Formeister et al., 2022). In a secondary analysis, the authors note that the reports per 100,000 doses in VAERS decreased from 1.10 in December 2020 to 0.01 in June 2021, despite large increases in the absolute number of vaccines administered. From Evidence to Conclusions The broader academic literature includes a handful of published articles reporting sudden sensorineural hearing loss (SSNHL) in individuals receiving COVID-19 vaccination; however, this level of evidence does not support an association between vaccination and SSNHL (Formeister et al., 2022; Jeong and Choi, 2021; Tsetsos et al., 2021). However, the committee found that the majority of the literature was limited to single case reports, unadjusted descriptive reports lacking a comparison or without thoughtful adjudication of hearing loss, or publications with potential bias and these did not meet our inclusion criteria during screening. Only one of the studies included in this review suggested an association between COVID-19 vaccination and SSNHL. However, the magnitude of the effect was small, with potential for confounding from unmeasured variables. In contrast, the most methodologically rigorous analysis that included potential confounders (e.g., infection status, comorbidities, and health care use patterns) in models found no association. Using pharmacovigilance data without comparators offers low- level evidence to support a conclusion. Nonetheless, one article used VAERS data and offered compelling evidence that incidence of SSNHL were similar to expected rates and much lower after an adjudication procedure to assess the credibility of the reported hearing loss. Moreover, the same report showed that the weekly number of reports of SSNHL did not change over time despite large increases in the number of vaccines administered. An emergent theme is heterogeneity in identification of SSNHL and potential for misclassification. First, self-reported data may be unreliable. Insights from the reviewed literature may reflect this. Formeister et al. (2022) offered insights that many reports of SSNHL in the VAERS data may not be true cases, and Leong et al. (2023) found that the majority of self- reported new cases from vaccination were attributable to exacerbating known etiologies of hearing loss. Another consideration may be that hearing includes peripheral encoding and central PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 121 processing of information in the brain, and cognitive processes play a key role in how individuals understand speech. The role of cognition in the potential association between self-reported hearing and COVID-19 infection or vaccination may be highly overlooked, as it is plausible that existing age-related hearing loss, which is highly prevalent, could be perceived as “new” due to fatigue or “brain fog.” Second, studies varied in definitions of SSNHL, including using different risk-windows. Moreover, different and unverified approaches to diagnosis codes were used. Two studies used diagnosis codes. Yanir et al. (2022) took a wide approach by looking for many different ICD codes for hearing loss with concurrent prednisone usage; Nieminen et al. (2023) used a single SSNHL code. Given the acute nature of SSNHL, diagnosis codes may be accurate and reliable with some suggestion that an audiological test battery occurred. However, it is unknown if concurrent ICD codes for more general hearing loss paired with prednisone use is reliable. No studies examined the relationship between NVX-CoV2373 3 and SSNHL. Overall, we found that the literature on vaccination and sensorineural hearing loss focused almost exclusively on SSNHL. Our review of said literature resulted in weak evidence and concerns about the measurement of SSNHL. Although the combination of the more methodologically rigorous evidence suggesting no association and lack of identified potential mechanisms beyond hypotheses may hint at no relationship between vaccination and SSNHL, the literature is inadequate to offer a decision on the acceptance or rejection of a causal relationship. Future epidemiological evidence is required. Conclusion 4-1: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and sensorineural hearing loss. Conclusion 4-2: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and sensorineural hearing loss. Conclusion 4-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and sensorineural hearing loss. Conclusion 4-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and sensorineural hearing loss. 3 Refers to the COVID-19 vaccine manufactured by Novavax. PREPUBLICATION COPY: Uncorrected Proofs

122 VACCINE EVIDENCE REVIEW TINNITUS BOX 4-2 Conclusions for Tinnitus Conclusion 4-5: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and tinnitus. Conclusion 4-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and tinnitus. Conclusion 4-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and tinnitus. Conclusion 4-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and tinnitus. Background Tinnitus is the phenomenon of perceiving sound without an external stimulus. The sound can be continuous or intermittent. Reported descriptions range (e.g., ringing, buzzing, hissing, pulsation, clicks) and reported acoustic characteristics range in amplitude (volume) and frequency (pitch) (Baguley et al., 2013; Lockwood et al., 2002). Prevalence estimates vary (4.6– 30 percent) due to heterogeneity in measures and studies are mostly limited to North America and Europe (Baguley et al., 2013; Lockwood et al., 2002; McCormack et al., 2016). A meta- analysis of 113 articles estimated the pooled prevalence of tinnitus and suggests that 14.4 percent of adults report it (Jarach et al., 2022). However, this estimate varied by definition of tinnitus and dropped to 3.4 percent for diagnosed tinnitus (as opposed to self-reported). Prevalence increases with age; 23.6 percent of older adults report tinnitus. The pooled incidence rate of any tinnitus was 1,164 per 100,000 person-years (Jarach et al., 2022). Tinnitus is considered a symptom of an underlying condition rather than a disease. Risk factors are broad and include occupational (e.g., noise exposure), muscular tension, neurological, trauma, cardiovascular, rheumatological, psychological, endocrinological, metabolic, and pharmacological conditions and factors (Baguley et al., 2013; Koning, 2021; Lockwood et al., 2002; Pezzoli et al., 2015). Overarching hypotheses (Roberts et al., 2013) on the cause are that a lack of sensory stimulation due to hearing loss (bottom-up) leads to reorganization and changes in neural firing/synchrony in neural networks that are responsible for limbic, attention, and audition (top-down) resulting in perceived sound. Clinical consensus is that peripheral hearing loss, particularly when the origin is noise-induced, is the most common source of tinnitus (Baguley et al., 2013; Lockwood et al., 2002; Piccirillo et al., 2020). Without an objective measure, tinnitus diagnosis relies on a combination of patient- reported perceived sound characteristics, subjective impact on quality of life and well-being, medical history review, and accompanying assessments to uncover the etiology (Baguley et al., 2013; Bhatt et al., 2016; Langguth et al., 2013). Validated tinnitus questionnaires play a key role in offering a standardized characterization, and comprehensive audiometric testing should be PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 123 performed to assess the function of the auditory system for potential sources of the symptom (e.g., hearing loss). Imaging is employed to investigate the source of tinnitus in complex cases, especially for asymmetric tinnitus, concurrent associated neurological symptoms, and pulsatile tinnitus (Baguley et al., 2013; Bhatt et al., 2016; Langguth et al., 2013). Mechanisms Tinnitus etiology is multifactorial, encompassing neural, vascular, muscular, and metabolic processes, and often influenced by environmental factors. Moreover, tinnitus may differ by predisposing risk factors, and the individual reactions to it differ by anxiety levels, which may influence reporting of the symptom and perceived impact. An important consideration is that tinnitus is a symptom of other conditions. It primarily involves the peripheral and central auditory systems, with the prevailing theory that it results from altered neuronal activity within the auditory pathway secondary to peripheral hearing loss, leading to a reduction in afferent input to the central auditory system. The brain compensates for this loss by increasing the gain in the central auditory pathways, a phenomenon known as “central gain.” This heightened sensitivity and neuronal hyperactivity can manifest as the perception of sound (Makar, 2021). Therefore, a proposed mechanistic relationship between tinnitus and vaccination includes potential for it as a secondary symptom of vaccine-induced hearing loss. However, as noted, mechanistic evidence linking hearing loss and COVID-19 vaccination is limited. Vaccines can occasionally lead to adverse effects, including reported cases of tinnitus. Little direct evidence exists for a direct link, but hypotheses appear in the literature; these mechanisms are not fully understood but thought to involve immune-mediated responses. One hypothesis is molecular mimicry, where the immune response against vaccine components cross- reacts with inner ear antigens, leading to inflammation and damage. Similarly, an autoimmune response triggered by the vaccine (e.g., type 3 hypersensitivity) may manifest as autoimmune inner ear disease in susceptible individuals (Kamogashira et al., 2022). Less-well-described mechanisms involve toxic responses from vaccine components or restricted cochlear blood flow (Ahmed et al., 2022). Although the previous mechanisms focus on a bottom-up insult leading to tinnitus, top- down changes resulting from vaccination are hypothetical. In common theories of tinnitus, neuroplastic changes occur in the neuronal activity of the auditory cortex, thalamus, and other related brain areas after peripheral injury that reduces sensory input. These changes can include increased spontaneous firing rates, enhanced neural synchrony, and reorganization of the auditory cortex. These neural alterations are thought to contribute to the persistence and severity of tinnitus (Ahmed et al., 2022, Baguley et al., 2013, Ciorba et al., 2018, Piccirillo et al., 2020). Proinflammatory cytokines, immune responses, and other inflammatory mediators could exacerbate neural damage (Becker et al., 2022) and contribute to the development of vaccine- mediated tinnitus. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding tinnitus and any of the vaccines under study (FDA, PREPUBLICATION COPY: Uncorrected Proofs

124 VACCINE EVIDENCE REVIEW 2021, 2023a, 2023b, 2023c). Table 4-2 presents four studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 125 TABLE 4-2 Epidemiological Studies in the Tinnitus Evidence Review Study Design and Number Control Data Age of Results Author Group Location Source Vaccine(S) Range N Events (95% CI) 167.0 Median 13.53 per 1 million BNT162b2 age = million doses doses 50 years Frontera 128.1 Surveillance IQR 35– Not 13.90 per 1 et al. US VAERS mRNA-1273 million ; single arm 64 for all reported million doses (2022) doses neurologic adverse 11.6 51.52 per 1 Ad26.COV2.S events million million doses doses The 1 serious, Relatively low Netherla BNT162b2 12,888 18 non- incidence of nds Kant et serious tinnitus cases Surveillance Netherlan Pharmac 12 to >80 al. 7 non- reported but no ; single arm ds ovigilan mRNA-1273 years 3,426 (2022) serious comparison ce group included Centre 8 non- Ad26.COV2.S 2,458 for inference Lareb serious BNT162b2 244 1.9% of Otology 16 vaccinated Clinical Leong at clinic at 16–101 individuals had convenience NY, NY, al. academi mRNA-1273 years 123 adjudicated new sample; USA 8 (2023) c center or not otherwise Single arm explained Ad26.COV2.S 16 1 tinnitus PREPUBLICATION COPY: Uncorrected Proofs

126 VACCINE EVIDENCE REVIEW TABLE 4-2 Continued Study Design and Number Control Data Age of Results Author Group Location Source Vaccine(s) Range N Events (95% CI) Pre-vaccination: Electron Pre- 100.8 (89.6– ic Vaccinat 113.0) per Health Unspecified ion: 294 100,000 person- Records percentages Population- events weeks from but included Whittak based England, Clinical any of three 18 to >80 er et al. retrospective 267,993 Post Post- UK Practice approved years (2021) cohort; pre Vaccinat vaccination: Researc COVID-19 and post ion: 69 41.8 (32.5–52.8) h vaccines in the events per 100,000 Datalink UK person-weeks Aurum database NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. Number of events refers to events in vaccinees only. IQR: interquartile range; IR: incidence rate; VAERS: Vaccine Adverse Event Reporting System. SOURCES: Frontera et al., 2022; Kant et al., 2022; Leong et al., 2023; Whittaker et al., 2021. PREPUBLICATION COPY—Uncorrected Proofs

HEARING LOSS AND TINNITUS 127 Leong et al. (2023) leveraged a convenience sample from an otology clinic in a large, urban medical center (NYC, NY) from May to July 2021 to characterize the incidence of hearing loss after COVID-19 vaccination. Among 500 individuals who completed screening (median age 56.6 years; 40.2 percent female), 420 reported being vaccinated (58.4 percent BNT162b2, 29.1 percent mRNA-1273, 3.8 percent Ad26.COV2.S), and 26 of these (all vaccinees) (6.2 percent) reported tinnitus. However, after audiologic and medical evaluation, 10 cases were attributed to hearing loss and eight to other conditions (e.g., temporomandibular joint syndrome, otitis media, and earwax), resulting in eight (1.9 percent) individuals with subjective tinnitus as the primary diagnosis. Whittaker et al. (2021) conducted a population-based study using electronic health records data from 1,392 general practices in England contributing to the Clinical Practice Research Datalink AURUM database (August 2020–May 2021) to describe rates of consulting a general practitioner for new symptoms, diseases, prescriptions, and health care use among adults after diagnosis of COVID-19. Adults with evidence of outcomes of interest before COVID-19 diagnosis were excluded. In the study, 267,993 individuals who had a COVID-19 diagnosis and were managed in the community were vaccinated during the follow-up period. Among this group, the estimated incidence of tinnitus events dropped from 100.8 (range 89.6–113.0) pre- vaccination to 41.8 (range 32.5–52.8) post-vaccination per 100,000 person-weeks; an analysis adjusted for age, sex, smoking, BMI, and the Charlson Comorbidity Index found a decrease in incidence of tinnitus events after vaccination (IRR 0.39, 95% CI: 0.25–0.59, p < 0.001). Two surveillance studies were included in the review. Frontera et al. (2022) used VAERS to examine adverse events after vaccination between January 1, 2021, and June 14, 2021 (306.9 million COVID-19 vaccine doses; 314,610 adverse events (71 percent female). They reported an incidence of 15.14 cases of tinnitus identified by free text or automated coding per 1,000,000 vaccines (13.53 BNT162b2, 13.90 mRNA-1273, 51.52 Ad26.COV2.S). Kant et al. (2022) recruited participants within 2 days of vaccination at sites across the Netherlands for a Web-based surveillance study of self-reported adverse events using closed and open questionnaires. They analyzed adverse events within 7 days of first and second dose (if applicable). Among the 27,554 events, one serious and 33 nonserious occurrences of tinnitus were reported. Events were coded as serious or not according to the Council for International Organizations of Medical Sciences criteria (Macrae, 2007) (CIOMS, 2010). Dorney et al. (2023) used data from a large, deidentified electronic health record database (TriNetX Analytics Network) from December 15, 2020, to March 1, 2022, to compare the prevalence of new-onset tinnitus (within 21 days) after COVID-19 vaccination relative to other common vaccines that are not suspected of causing tinnitus. Even though this paper did not use an unvaccinated control (and is therefore not included in Table 4-2), it is informative. Tinnitus was identified based on electronic health records data. The authors reported estimated 0.038 percent (95% CI: 0.036–0.041) prevalence and 0.031 percent (95% CI: 0.029–0.034) prevalence of new tinnitus after the first (n = 2.6 million) and second (n = 1.5 million) doses. The authors used propensity matching (age at vaccination, sex, race, and ethnicity) to compare the RR of new-onset tinnitus after other vaccines compared a first COVID-19 vaccine. The authors reported a higher RR of new-onset tinnitus after the influenza vaccine (998,991 vs. 1,009,935 first dose COVID-19 vaccine patients; mean age: 43.0 vs. 45.6 years; relative risk (RR) 1.95, 95% CI: 1.72–2.21), Tdap (444,708 vs. 444,721 first dose COVID-19 vaccine patients; mean age: 39.4 vs.40.3; RR 2.36, 95% CI: 1.93–2.89) and polysaccharide pneumococcus (154,344 vs. 154,825 first dose COVID-19 vaccine patients; mean age: 59.3 vs. 59.5 years; RR 1.97, 95% CI: PREPUBLICATION COPY: Uncorrected Proofs

128 VACCINE EVIDENCE REVIEW 1.48–2.64) vaccines, respectively. While this data does not offer direct evidence and any of the aforementioned vaccines being associated with new onset tinnitus, it does suggest that COVID- 19 vaccination does not have any higher risk of new onset tinnitus compared to common vaccines that are not suspected of causing tinnitus. From Evidence to Conclusions Several case reports appear in the academic literature and media of tinnitus after COVID- 19 vaccination. However, the epidemiological evidence review offered limited insight. Three surveillance and clinical sample studies suggest relatively low incidence after vaccination but lack comparator groups for inferential conclusions and suffer from biases, particularly selection, and confounding. Other studies offered valuable insights but were limited in scope and indirectly addressed the question. Dorney et al. (2023) found onset of tinnitus was lower after COVID-19 vaccination relative to other common vaccinations, and Whittaker et al. (2021) found that vaccination reduced the incidence of tinnitus as a reason for general practitioner visits among individuals who had been diagnosed with COVID-19. However, while these studies met inclusion criteria, inherent flaws in the study designs or limitations to the reference group limit any conclusive evidence. Of further concern, the heterogeneity in tinnitus etiology, pathophysiology, and characteristics combined with no objective diagnostic measure or standardized subjective measure make it difficult to assess a relationship with vaccination. Despite several hypotheses, no definitive mechanistic evidence was identified in the literature. The nature of tinnitus as a symptom of other conditions further complicates a review of the data, as it is plausible for it to be a symptom of conditions potentially caused by vaccination, but it is unclear how this is reflected in the measurement of tinnitus across studies. Leong et al. (2023) does offer some insight into this: 18 of 26 cases were attributable to other conditions after medical evaluation. Conclusion 4-5: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and tinnitus. Conclusion 4-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and tinnitus. Conclusion 4-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and tinnitus. Conclusion 4-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and tinnitus. PREPUBLICATION COPY—Uncorrected Proofs

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 Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

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